allosteric site

Summary

Summary: A site on an enzyme which upon binding of a modulator, causes the protein to undergo a conformational change that may alter the catalytic or binding properties of the enzyme.

Top Publications

  1. ncbi Structural Basis of allosteric regulation and substrate specificity of the non-phosphorylating glyceraldehyde 3-Phosphate dehydrogenase from Thermoproteus tenax
    Esben Lorentzen
    European Molecular Biology Laboratory, Hamburg Outstation, Notkestr 85, D 22603 Hamburg, Germany
    J Mol Biol 341:815-28. 2004
  2. pmc ASD: a comprehensive database of allosteric proteins and modulators
    Zhimin Huang
    The Department of Pathophysiology, Chemical Biology Division, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Universities E Institutes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Nucleic Acids Res 39:D663-9. 2011
  3. ncbi Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain
    Natalie K Goto
    Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 277:43168-74. 2002
  4. pmc Surface sites for engineering allosteric control in proteins
    Jeeyeon Lee
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Science 322:438-42. 2008
  5. ncbi BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice
    James R Burke
    Department of Immunology, Inflammation and Pulmonary Drug Discovery, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
    J Biol Chem 278:1450-6. 2003
  6. ncbi Allosteric modulation of G protein-coupled receptors
    Lauren T May
    Department of Pharmacology, University of Melbourne, 3010 Parkville, Victoria
    Annu Rev Pharmacol Toxicol 47:1-51. 2007
  7. pmc Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias
    Karen J Gregory
    Department of Pharmacology, Monash University, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
    J Biol Chem 285:7459-74. 2010
  8. pmc A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand
    Celine Valant
    Drug Discovery Biology Laboratory, Monash University, 3800 Victoria, Australia
    J Biol Chem 283:29312-21. 2008
  9. ncbi Allosteric small molecules unveil a role of an extracellular E2/transmembrane helix 7 junction for G protein-coupled receptor activation
    Dorothea Jäger
    Pharmacology and Toxicology Section, Institute of Pharmacy, Rheinische Friedrich Wilhelms University, D 53121 Bonn, Germany
    J Biol Chem 282:34968-76. 2007
  10. pmc Novel allosteric sites on Ras for lead generation
    Barry J Grant
    Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 6:e25711. 2011

Detail Information

Publications244 found, 100 shown here

  1. ncbi Structural Basis of allosteric regulation and substrate specificity of the non-phosphorylating glyceraldehyde 3-Phosphate dehydrogenase from Thermoproteus tenax
    Esben Lorentzen
    European Molecular Biology Laboratory, Hamburg Outstation, Notkestr 85, D 22603 Hamburg, Germany
    J Mol Biol 341:815-28. 2004
    ..3 A resolution, which allows us to analyse the structural basis for substrate binding, the mechanism of catalysis as well as the stereoselectivity of the enzymatic reaction...
  2. pmc ASD: a comprehensive database of allosteric proteins and modulators
    Zhimin Huang
    The Department of Pathophysiology, Chemical Biology Division, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Universities E Institutes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Nucleic Acids Res 39:D663-9. 2011
    ..Therefore, ASD could be a platform and a starting point for biologists and medicinal chemists for furthering allosteric research. ASD is freely available at http://mdl.shsmu.edu.cn/ASD/...
  3. ncbi Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain
    Natalie K Goto
    Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 277:43168-74. 2002
    ..In the case of MLL and c-Myb, both proteins are involved in proliferation of hematopoietic cells and leukemogenesis, and synergistic interactions mediated by CBP may play a functional role...
  4. pmc Surface sites for engineering allosteric control in proteins
    Jeeyeon Lee
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Science 322:438-42. 2008
    ..PAS-DHFR serves as a proof of concept for engineering regulatory activities into proteins through interface design at conserved allosteric sites...
  5. ncbi BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice
    James R Burke
    Department of Immunology, Inflammation and Pulmonary Drug Discovery, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
    J Biol Chem 278:1450-6. 2003
    ..Thus, the compound is effective against NF-kappa B activation in mice and represents an important tool for investigating the role of IKK in disease models...
  6. ncbi Allosteric modulation of G protein-coupled receptors
    Lauren T May
    Department of Pharmacology, University of Melbourne, 3010 Parkville, Victoria
    Annu Rev Pharmacol Toxicol 47:1-51. 2007
    ..Studies are also beginning to unravel the structural basis of allosteric modulation of GPCRs. It remains to be determined whether such modulation represents interactions within monomers versus across dimers...
  7. pmc Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias
    Karen J Gregory
    Department of Pharmacology, Monash University, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
    J Biol Chem 285:7459-74. 2010
    Muscarinic acetylcholine receptors contain at least one allosteric site that is topographically distinct from the acetylcholine, orthosteric binding site...
  8. pmc A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand
    Celine Valant
    Drug Discovery Biology Laboratory, Monash University, 3800 Victoria, Australia
    J Biol Chem 283:29312-21. 2008
    ....
  9. ncbi Allosteric small molecules unveil a role of an extracellular E2/transmembrane helix 7 junction for G protein-coupled receptor activation
    Dorothea Jäger
    Pharmacology and Toxicology Section, Institute of Pharmacy, Rheinische Friedrich Wilhelms University, D 53121 Bonn, Germany
    J Biol Chem 282:34968-76. 2007
    ..we found that the deviating allosteric/orthosteric interactions are mediated through the core region of the allosteric site. A key epitope is M(2)Trp(422) in position 7...
  10. pmc Novel allosteric sites on Ras for lead generation
    Barry J Grant
    Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 6:e25711. 2011
    ..We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs...
  11. ncbi Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics
    Tsan Xiao
    The CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
    Nature 432:59-67. 2004
    ..Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface...
  12. pmc Coherent conformational degrees of freedom as a structural basis for allosteric communication
    Simon Mitternacht
    Computational Biology Unit UNI Research, University of Bergen, Bergen, Norway
    PLoS Comput Biol 7:e1002301. 2011
    ..Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites...
  13. pmc Exploiting protein flexibility to predict the location of allosteric sites
    Alejandro Panjkovich
    Institute of Biotechnology and Biomedicine, Universitat Autonoma de Barcelona, 08193 Cerdanyola del Valles, Spain
    BMC Bioinformatics 13:273. 2012
    ..In this article, we describe a simple computational approach, based on the effect allosteric ligands exert on protein flexibility upon binding, to predict the existence and position of allosteric sites on a given protein structure...
  14. ncbi The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors
    Celine Valant
    Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia
    Annu Rev Pharmacol Toxicol 52:153-78. 2012
    ..Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated...
  15. pmc Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor
    Samuel Murail
    Department of Theoretical Physics, Royal Institute of Technology, Stockholm, Sweden
    Biophys J 100:1642-50. 2011
    ..Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors...
  16. pmc Allostery is an intrinsic property of the protease domain of DegS: implications for enzyme function and evolution
    Jungsan Sohn
    Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    J Biol Chem 285:34039-47. 2010
    ..Thus, substrate binding alone may have regulated the activities of ancestral DegS trimers with subsequent fusion of the protease domain to a PDZ domain, resulting in ligand-mediated regulation...
  17. ncbi Allosteric disulfide bonds
    Bryan Schmidt
    Centre for Vascular Research, University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, New South Wales 2052, Australia
    Biochemistry 45:7429-33. 2006
    ..We suggest that the -RHStaple configuration is a hallmark of allosteric disulfides. About 1 in 15 of all structurally determined disulfides is a potential allosteric bond...
  18. ncbi Correlating allostery with rigidity
    A J Rader
    Department of Physics, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
    Mol Biosyst 7:464-71. 2011
    ..Thus structural rigidity is shown to be a fundamental underlying property that promotes cooperativity and non-locality seen in allostery...
  19. pmc Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
    Jill C Milne
    Sirtris Pharmaceuticals Inc, 790 Memorial Drive, Cambridge, Massachusetts 02139, USA
    Nature 450:712-6. 2007
    ..These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates...
  20. ncbi Allosteric modulation of G protein-coupled receptors: a pharmacological perspective
    Peter Keov
    Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia
    Neuropharmacology 60:24-35. 2011
    ..The ever-expanding array of allosteric modulators arising from both academic and industrial research also highlights the need for the development of a uniform approach to nomenclature of such compounds...
  21. ncbi Searching for new allosteric sites in enzymes
    Jeanne A Hardy
    Sunesis Pharmaceuticals Inc, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA
    Curr Opin Struct Biol 14:706-15. 2004
    ..By exploring recent structurally well-characterized examples, trends begin to emerge for both the modes of binding and mechanisms of inhibition...
  22. pmc Allostery and cooperativity revisited
    Qiang Cui
    Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin, Madison, Wisconsin 53706, USA
    Protein Sci 17:1295-307. 2008
    ..The presentation offers not only an up-to-date description of allostery from a theoretical/computational perspective, but also helps to resolve several outstanding issues concerning allostery...
  23. pmc CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations
    John W Scott
    Division of Molecular Physiology, Faculty of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Scotland, United Kingdom
    J Clin Invest 113:274-84. 2004
    ..This shows that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a newly identified class of binding domain for adenosine derivatives...
  24. pmc Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach
    Anthony Ivetac
    Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
    Chem Biol Drug Des 76:201-17. 2010
    ..This mapping data can now serve to drive a combination of fragment-based and virtual screening approaches for the discovery of small molecules that bind at these sites and which may offer highly selective therapies...
  25. ncbi Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression
    Wade Winkler
    Department of Molecular, Cellular and Developmental Biology, Yale University, PO Box 208103, New Haven, Connecticut 06520 8103, USA
    Nature 419:952-6. 2002
    ..This metabolite-sensing regulatory system provides an example of a 'riboswitch' whose evolutionary origin might pre-date the emergence of proteins...
  26. ncbi Phosphoenolpyruvate carboxylase: three-dimensional structure and molecular mechanisms
    Yasushi Kai
    Department of Materials Chemistry, Graduate School of Engineering, Osaka University, Suita, 565 0871, Osaka, Japan
    Arch Biochem Biophys 414:170-9. 2003
    ..Information derived from these three-dimensional structures, combined with related biochemical studies, has established models for the reaction mechanism and allosteric regulation of this important C-fixing enzyme...
  27. ncbi Amide hydrogen exchange reveals conformational changes in hsp70 chaperones important for allosteric regulation
    Wolfgang Rist
    Zentrum für Molekulare Biologie der Universität Heidelberg ZMBH, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
    J Biol Chem 281:16493-501. 2006
    ..ATP reverts the ATP-induced conformational changes in the linker and selected parts of the NBD. Our data outline a pathway for allosteric interdomain control and suggest an important role of the linker and the base of helix alphaA...
  28. ncbi Allostery and conformational free energy changes in human tryptophanyl-tRNA synthetase from essential dynamics and structure networks
    Moitrayee Bhattacharyya
    Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
    Proteins 78:506-17. 2010
    ..The methodology adopted here is highly generalized to illuminate the linkage between protein structure networks and conformational mobility involved in the allosteric mechanism in any protein with known structure...
  29. ncbi Allosite: a method for predicting allosteric sites
    Wenkang Huang
    Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Bioinformatics 29:2357-9. 2013
    ..Allosite is a newly developed automatic tool for the prediction of allosteric sites in proteins of interest and is now available through a web server...
  30. ncbi Structural consequences of effector binding to the T state of aspartate carbamoyltransferase: crystal structures of the unligated and ATP- and CTP-complexed enzymes at 2.6-A resolution
    R C Stevens
    Gibbs Chemical Laboratory, Harvard University, Cambridge, Massachusetts 02138
    Biochemistry 29:7691-701. 1990
    ..We observe a higher occupancy for ATP in the allosteric site of the R1 regulatory chain in comparison to the occupancy of the R6 allosteric site...
  31. ncbi Toward an understanding of the sequence and structural basis of allosteric proteins
    XiaoBai Li
    Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University, School of Medicine, Shanghai 200025, China
    J Mol Graph Model 40:30-9. 2013
    ..These results may be of great significance in predicting which proteins are allosteric and in designing novel triggers to inhibit or activate proteins of interest...
  32. pmc Anionic lipids allosterically modulate multiple nicotinic acetylcholine receptor conformational equilibria
    Corrie J B daCosta
    Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
    J Biol Chem 284:33841-9. 2009
    ....
  33. ncbi The different ways through which specificity works in orthosteric and allosteric drugs
    Ruth Nussinov
    NCI Frederick Bldg, Frederick, MD 21702, USA
    Curr Pharm Des 18:1311-6. 2012
    ..We provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development...
  34. ncbi Toward understanding the molecular basis for chemical allosteric modulator design
    Qi Wang
    School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
    J Mol Graph Model 38:324-33. 2012
    ..Therefore, the study provides deeper insight into the chemical properties of allosteric modulators and has a good potential for the design or optimization of allosteric compounds...
  35. ncbi Simulations of allosteric transitions
    Ron Elber
    Department of Chemistry and Biochemistry, Institute of Computational Engineering and Sciences, 1 University Station, ICES, C0200, The University of Texas at Austin, Austin, TX 78712, USA
    Curr Opin Struct Biol 21:167-72. 2011
    ..In the present review we examined different theoretical and computational attempts to solve the questions...
  36. pmc Turning a protein kinase on or off from a single allosteric site via disulfide trapping
    Jack D Sadowsky
    Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, 1700 Fourth Street, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 108:6056-61. 2011
    ..we apply a site-directed technology, disulfide trapping, to interrogate structurally and functionally how an allosteric site on the Ser/Thr kinase, 3-phosphoinositide-dependent kinase 1 (PDK1)--the PDK1-interacting-fragment (PIF) ..
  37. pmc A fluorescence resonance energy transfer-based M2 muscarinic receptor sensor reveals rapid kinetics of allosteric modulation
    Monika Maier-Peuschel
    Institute of Pharmacology and Toxicology and the Rudolf Virchow Center, University of Wurzburg, 97078 Wurzburg, Germany
    J Biol Chem 285:8793-800. 2010
    ....
  38. pmc Allosteric vs. spontaneous exit-site (E-site) tRNA dissociation early in protein synthesis
    Chunlai Chen
    Pennsylvania Muscle Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 6083, USA
    Proc Natl Acad Sci U S A 108:16980-5. 2011
    ....
  39. ncbi Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities
    Marco De Amici
    Department of Pharmaceutical Sciences Pietro Pratesi, University of Milan, Via Mangiagalli 25, 20133 Milano, Italy
    Med Res Rev 30:463-549. 2010
    ..In addition, the behavior at muscarinic receptors of hybrid derivatives incorporating both an allosteric and an orthosteric fragment in a common molecular skeleton will be illustrated...
  40. ncbi Allosteric interactions with muscarinic acetylcholine receptors: complex role of the conserved tryptophan M2422Trp in a critical cluster of amino acids for baseline affinity, subtype selectivity, and cooperativity
    Stefanie Prilla
    Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, 53121 Bonn Germany
    Mol Pharmacol 70:181-93. 2006
    ..Thus, M2 422Trp and the spatially adjacent M2 177Tyr, as well as M2 423Thr, form a cluster of amino acids within the allosteric binding cleft that is pivotal for both M2/M5 subtype selectivity and baseline affinity of allosteric agents...
  41. ncbi Modeling the cAMP-induced allosteric transition using the crystal structure of CAP-cAMP at 2.1 A resolution
    J M Passner
    Department of Molecular Biophysics and Biochemistry, Mount Sinai Schoolof Medicine, New York, NY 10029, USA
    J Mol Biol 304:847-59. 2000
    ..Additionally, cAMP binding may cause a further rearrangement of the DNA-binding and cAMP-binding domains of CAP via a flap consisting of beta-strands 4 and 5 which lies over the cAMP...
  42. pmc Conopeptide ρ-TIA defines a new allosteric site on the extracellular surface of the α1B-adrenoceptor
    Lotten Ragnarsson
    Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
    J Biol Chem 288:1814-27. 2013
    ..receptor crystal structure, we modeled the α(1B)-adrenoceptor (α(1B)-AR) to help identify the allosteric site for ρ-conopeptide TIA, an inverse agonist at this receptor...
  43. pmc Computation of conformational coupling in allosteric proteins
    Brian A Kidd
    Department of Bioengineering, University of Washington, Seattle, Washington, United States of America
    PLoS Comput Biol 5:e1000484. 2009
    ....
  44. ncbi Molecular mechanism for ligand discrimination of cyclic nucleotide-gated channels
    M D Varnum
    Department of Physiology and Biophysics, Seattle 98195, USA
    Neuron 15:619-25. 1995
    ....
  45. pmc Allosteric modulation of Ras positions Q61 for a direct role in catalysis
    Greg Buhrman
    Department of Molecular and Structural Biochemistry, North Carolina State University, 128 Polk Hall CB 7622, Raleigh, NC 27695, USA
    Proc Natl Acad Sci U S A 107:4931-6. 2010
    ..We propose that Raf together with the binding of Ca(2+) and a negatively charged group mimicked in our structure by the acetate molecule induces the ordering of switch I and switch II to complete the active site of Ras...
  46. pmc Kinetic, mechanistic, and structural aspects of unliganded gating of acetylcholine receptor channels: a single-channel study of second transmembrane segment 12' mutants
    C Grosman
    Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, USA
    J Gen Physiol 115:621-35. 2000
    ..Such increase is independent of the particular ligand used as the agonist, which suggests that these mutations affect mostly the isomerization step, having little, if any, effect on the ligand-affinity ratio...
  47. pmc Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery
    Alejandro Panjkovich
    Institute of Biotechnology and Biomedicine IBB, Universitat Autonoma de Barcelona UAB, Bellaterra, E 08193, Spain
    BMC Struct Biol 10:9. 2010
    ..A first step in this direction is to identify and characterize putative effector sites that may be present in already available structural data...
  48. ncbi Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery
    Wolfgang Jahnke
    Center for Proteomic Chemistry and Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Nat Chem Biol 6:660-6. 2010
    ..These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment-based approaches using NMR and X-ray crystallography...
  49. ncbi Allosteric site on muscarinic acetylcholine receptors: identification of two amino acids in the muscarinic M2 receptor that account entirely for the M2/M5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine-occupie
    Uta Voigtländer
    Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany
    Mol Pharmacol 64:21-31. 2003
    ..M2-Tyr177 and M2-Thr423 seem to be located near the junction of the allosteric and the orthosteric areas of the M2 receptor ligand binding cavity...
  50. ncbi Pharmacology of the beta-carboline FG-7,142, a partial inverse agonist at the benzodiazepine allosteric site of the GABA A receptor: neurochemical, neurophysiological, and behavioral effects
    Andrew K Evans
    University of Bristol, Henry Wellcome Laboratories of Integrative Neuroscience and Endocrinology, Bristol, UK
    CNS Drug Rev 13:475-501. 2007
    ..beta-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABA(A) receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related ..
  51. pmc Structure-based predictive models for allosteric hot spots
    Omar N A Demerdash
    Biophysics Program, University of Wisconsin Madison, Madison, Wisconsin, United States of America
    PLoS Comput Biol 5:e1000531. 2009
    ..Moreover, the pattern of predicted hotspots corresponds to known functional motifs implicated in allostery, and is consistent with previous work describing sparse networks of allosterically important residues...
  52. pmc Trapping moving targets with small molecules
    Gregory M Lee
    Department of Pharmaceutical Chemistry, University of California, San Francisco UCSF, 600 16th Street, Box 2280, San Francisco, CA 94158 2280, USA
    Science 324:213-5. 2009
    ..Although multiple methodologies exist to probe protein dynamics and ligand binding, our current discussion highlights the use of nuclear magnetic resonance spectroscopy in the drug discovery and design process...
  53. ncbi Ionic contacts at DnaK substrate binding domain involved in the allosteric regulation of lid dynamics
    Vanesa Fernández-Sáiz
    Unidad de Biofisica Consejo Superior de Investigaciones Cientificas Universidad del Pais Vasco, Euskal Herriko Unibertsitatea, 48080 Bilbao, Spain
    J Biol Chem 281:7479-88. 2006
    ..These interactions also stabilize peptide-Hsp70 complexes at physiological (37 degrees C) and stress (42 degrees C) temperatures, a requirement for productive substrate (re)folding...
  54. ncbi Spectrochemical evidence for the presence of a tyrosine residue in the allosteric site of glucosamine-6-phosphate deaminase from Escherichia coli
    M M Altamirano
    Departamento de Bioquimica, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Distrito Federal, Mexico
    Eur J Biochem 220:409-13. 1994
    ..equilibrium to the R conformer), strongly suggests the presence of tyrosine residues at or near the allosteric site, although a conformational effect cannot be ruled out...
  55. ncbi Allosteric inhibition of protein tyrosine phosphatase 1B
    Christian Wiesmann
    Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA
    Nat Struct Mol Biol 11:730-7. 2004
    ..Here we describe the discovery of an allosteric site in PTP1B...
  56. pmc Kinetic and structural investigations of the allosteric site in human epithelial 15-lipoxygenase-2
    Aaron T Wecksler
    Chemistry and Biochemistry Department, University of California, Santa Cruz, California 95064, USA
    Biochemistry 48:8721-30. 2009
    ..of a 15-hLO-2 homology model and found to bind well with H627, suggesting a potential location for the allosteric site. Utilizing d31-LA as an inhibitor, it was demonstrated that the binding of d31-LA to the allosteric site ..
  57. ncbi G protein-coupled receptor allosterism and complexing
    Arthur Christopoulos
    Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia
    Pharmacol Rev 54:323-74. 2002
    ..It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies...
  58. ncbi Looking for a sequence based allostery definition: a statistical journey at different resolution scales
    Saritha Namboodiri
    State Inter University Centre of Excellence in Bioinformatics, University of Kerala, Kariyavattom Campus, Thiruvananthapuram, Kerala, India
    J Theor Biol 304:211-8. 2012
    ..These free-energy-transfer hydrophobicity-based RQA markers when evaluated by pattern recognition tools could distinguish allosteric proteins with 92% accuracy...
  59. ncbi Site-directed fluorescence labeling reveals differences on the R-conformer of glucosamine 6-phosphate deaminase of Escherichia coli induced by active or allosteric site ligands at steady state
    Alejandro Sosa-Peinado
    Departamento de Bioquimica, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, P O Box 70 159, Mexico, DF 04510, Mexico
    Biochemistry 44:15083-92. 2005
    ..changes were detected by the fluorescence emission spectra at steady state when the active site or the allosteric site ligands were titrated...
  60. pmc Impact of quaternary structure dynamics on allosteric drug discovery
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
    Curr Top Med Chem 13:55-63. 2013
    ..Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics...
  61. pmc Dynamic allostery in the methionine repressor revealed by force distribution analysis
    Wolfram Stacklies
    CAS MPG Partner Institute for Computational Biology, Key laboratory of Computational Biology, Chinese Academy of Sciences, Shanghai, China
    PLoS Comput Biol 5:e1000574. 2009
    ..Our results are in good agreement with experimental data. The force distribution analysis suggests itself as a valuable tool to gain insight into the molecular function of a whole class of allosteric proteins...
  62. pmc Identification of regions of rabbit muscle pyruvate kinase important for allosteric regulation by phenylalanine, detected by H/D exchange mass spectrometry
    Charulata B Prasannan
    Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, MS 3030, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, United States
    Biochemistry 52:1998-2006. 2013
    ..The set of allosterically relevant peptides identified by this technique includes residues previously identified by mutagenesis to have roles in allosteric regulation by phenylalanine...
  63. ncbi Structural insights into the architecture and allostery of full-length AMP-activated protein kinase
    Li Zhu
    MOE Key Laboratory of Arid and Grassland Ecology, Institute of Biophysics, Lanzhou University, Lanzhou 730000, P R China
    Structure 19:515-22. 2011
    ..These results not only make substantial revision to the current model of AMPK assembly, but also highlight a central role of the linker sequence of the α subunit in mediating the allostery of AMPK...
  64. ncbi Is allostery an intrinsic property of all dynamic proteins?
    K Gunasekaran
    Basic Research Program, SAIC Frederick, Inc, Laboratory of Experimental and Computational Biology, National Cancer Institute Frederick, Bldg 469, Rm 151, Frederick, Maryland 21702, USA
    Proteins 57:433-43. 2004
    ..The question is its effectiveness in the redistribution of the ensemble, affecting the protein binding sites and its function. Here, we review experimental observations validating this view of protein allostery...
  65. pmc Binding leverage as a molecular basis for allosteric regulation
    Simon Mitternacht
    Computational Biology Unit UNI Research, University of Bergen, Bergen, Norway
    PLoS Comput Biol 7:e1002148. 2011
    ..Because it is possible to calculate binding leverage from a single crystal structure it can be used for characterizing proteins of unknown function and predicting latent allosteric sites in any protein, with implications for drug design...
  66. ncbi The role of transmembrane domain 3 in the actions of orthosteric, allosteric, and atypical agonists of the M4 muscarinic acetylcholine receptor
    Katie Leach
    Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, 3052, Victoria, Australia
    Mol Pharmacol 79:855-65. 2011
    ....
  67. ncbi Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state
    Takashi Matsumoto
    PharmAxess, Inc, 3 9 12 Matsubara cho, Akishima, Tokyo 196 8666, Japan
    Biochem Biophys Res Commun 400:369-73. 2010
    ..These crystal structures revealed that the p38α peptide-bound npMKK4 at the allosteric site rather than at the putative substrate binding site and induced an auto-inhibition state...
  68. pmc Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor
    Gunnar Kleinau
    Leibniz Institut fur Molekulare Pharmakologie, Robert Rossle Str 10, D 13125 Berlin, Germany
    FASEB J 24:2347-54. 2010
    ..Our findings of signaling-sensitive residues in this region of the transmembrane bundle may be of general importance as this domain appears to be evolutionarily retained among GPCRs...
  69. pmc Impact of species variability and 'probe-dependence' on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor
    S Suratman
    Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Vic, Australia
    Br J Pharmacol 162:1659-70. 2011
    ..The current study investigated the basis for the species difference of this modulator and used this knowledge to rationalize its in vivo actions...
  70. pmc Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin
    A Berezov
    Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Oncogene 31:1938-48. 2012
    ..Thus, the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers...
  71. ncbi The nature of sites of general anaesthetic action
    K W Miller
    Department of Anaesthesia and Critical Care, Massachusetts General Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
    Br J Anaesth 89:17-31. 2002
    ..Bound anaesthetics generally exert their actions on ion channels by binding to allosteric sites whose topology varies from one conformation to another, but definitive proof for this mechanism remains elusive...
  72. ncbi Interactions of orthosteric and allosteric ligands with [3H]dimethyl-W84 at the common allosteric site of muscarinic M2 receptors
    Christian Tränkle
    Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Gerhard Domagk Strasse 3, D 53121 Bonn, Germany
    Mol Pharmacol 64:180-90. 2003
    An optimized assay for the binding of [3H]dimethyl-W84 to its allosteric site on M2 muscarinic receptors has been used to directly measure the affinities of allosteric ligands...
  73. ncbi The exploding field of the HCV polymerase non-nucleoside inhibitors: summary of a first generation compounds
    Enzo Tramontano
    Department of Sciences and Biomedical Technologies, University of Cagliari, Monserrato Cagliari, Italy
    Mini Rev Med Chem 8:1298-310. 2008
    ..All small molecules which have been identified to be selective non-nucleoside inhibitors (NNI) of the HCV RdRp to date are reported...
  74. pmc Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor
    Elodie Laine
    Institut Pasteur, Unité de Bioinformatique Structurale and Centre National de la Recherche Scientifique, Unité de Recherche Associée 2185, 25 28, rue du Dr Roux, 75 724 Paris, France
    Proc Natl Acad Sci U S A 107:11277-82. 2010
    ..The evolution of conformations along this path was used to identify a putative allosteric site that could regulate activation of Bacillus anthracis adenylyl cyclase toxin (EF) by calmodulin...
  75. ncbi Computational studies of LXR molecular interactions reveal an allosteric communication pathway
    Sofia Burendahl
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
    Proteins 80:294-306. 2012
    ..Thus, additional specificity between LXRα and its cofactors is likely to be found in molecular interactions outside the cofactor peptide or in other biological factors...
  76. ncbi Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands
    Laura H Heitman
    Division of Medicinal Chemistry, Leiden Amsterdam Center for Drug Research, University of Leiden, P O Box 9502, 2300 RA Leiden, The Netherlands
    Mol Cell Endocrinol 351:326-36. 2012
    ..The present study showed that these compounds are useful tools to reveal details on different allosteric binding sites located within the 7TMD of the LHCGR...
  77. ncbi Structure of the large subunit of class Ib ribonucleotide reductase from Salmonella typhimurium and its complexes with allosteric effectors
    Malin Uppsten
    Department of Molecular Biosciences section of Structure Biology, Uppsala Biomedical Center, Swedish University of Agricultural Sciences, Box 590, Sweden
    J Mol Biol 330:87-97. 2003
    ..The low affinity for ATP at the specificity site is explained by a tyrosine, which hinders nucleotides containing a 2'-OH group to bind...
  78. ncbi Critical amino acid residues of the common allosteric site on the M2 muscarinic acetylcholine receptor: more similarities than differences between the structurally divergent agents gallamine and bis(ammonio)alkane-type hexamethylene-bis-[dimethyl-(3-phtha
    Xi Ping Huang
    Department of Psychiatry, H073, Hershey Medical Center, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA
    Mol Pharmacol 68:769-78. 2005
    ..W84) are known to interact competitively at a common allosteric site on muscarinic receptors...
  79. ncbi Binding of orthosteric ligands to the allosteric site of the M(2) muscarinic cholinergic receptor
    Dar ya S Redka
    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada
    Mol Pharmacol 74:834-43. 2008
    The M(2) muscarinic receptor has two topographically distinct sites: the orthosteric site and an allosteric site recognized by compounds such as gallamine...
  80. ncbi A hydrazide linker strategy for heterobivalent compounds as ortho- and allosteric ligands of acetylcholine-binding proteins
    Paul W Elsinghorst
    Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D 53121 Bonn, Germany
    Curr Top Med Chem 11:2731-48. 2011
    ....
  81. ncbi A protein phosphorylation switch at the conserved allosteric site in GP
    K Lin
    Department of Biochemistry and Biophysics, University of California at San Francisco, 513 Parnassus, San Francisco, CA 94143, USA
    Science 273:1539-42. 1996
    ..The phosphorylated threonine is buried in the allosteric site. The mechanism implicates glucose 6-phosphate, the allosteric inhibitor, in facilitating dephosphorylation by ..
  82. pmc 3D-QSAR and 3D-QSSR models of negative allosteric modulators facilitate the design of a novel selective antagonist of human α4β2 neuronal nicotinic acetylcholine receptors
    Brandon J Henderson
    Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
    Bioorg Med Chem Lett 22:1797-813. 2012
    ..Additionally, information from the models presented in this work was used to synthesize novel molecules; which subsequently led to the discovery of a new selective antagonist of human α4β2 nAChRs...
  83. ncbi Isolation of an individual allosteric interaction in tetrameric phosphofructokinase from Bacillus stearothermophilus
    J L Kimmel
    Department of Biochemistry and Biophysics and Center for Advanced Biomolecular Research, Texas A and M University, 2128 TAMU, College Station, Texas 77843-2128, USA
    Biochemistry 40:11623-9. 2001
    ..of the system and thereby allow the quantitation of a single interaction between one active site and one allosteric site, site-directed mutagenesis has been coupled with a hybrid-forming scheme to create and isolate a tetramer of ..
  84. ncbi Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants
    Dai Shi Su
    Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, West Point, PA 19486, USA
    Bioorg Med Chem Lett 19:5119-23. 2009
    ..The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described...
  85. ncbi A geometry-based generic predictor for catalytic and allosteric sites
    Simon Mitternacht
    Computational Biology Unit, Bergen Center for Computational Science, Bergen, Norway
    Protein Eng Des Sel 24:405-9. 2011
    ..It is not biased towards typically catalytic residues, a property that is crucial when looking for non-catalytic effector sites, which are potent drug targets...
  86. ncbi Molecular design of artificial molecular and ion recognition systems with allosteric guest responses
    M Takeuchi
    Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, Fukuoka 812-8581, Japan
    Acc Chem Res 34:865-73. 2001
    ..In this Account, we account for our artificial allosteric systems and discuss the basic concept for molecular design of such allosteric systems and what kinds of new functions come out of such dynamic systems...
  87. ncbi Mechanism of ribosomal translocation. tRNA binds transiently to an exit site before leaving the ribosome during translocation
    J M Robertson
    Institute für Physiologische Chemie, Universitat Munchen, F R G
    J Mol Biol 196:525-40. 1987
    ..However, the E site can aid elongation by providing an intermediate state for tRNA dissociation, dispersing the process into more than one step...
  88. pmc A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties
    Eun Suk Song
    Department of Molecular and Cellular Biochemistry and the Center for Structural Biology, University of Kentucky, Lexington, Kentucky, United States of America
    PLoS ONE 5:e9719. 2010
    ..Insulin degrading enzyme (IDE) is a key enzyme in the metabolism of both insulin and amyloid beta peptides. IDE is unique in that it is subject to allosteric activation which is hypothesized to occur through an oligomeric structure...
  89. pmc Characterization of the functional role of allosteric site residue Asp102 in the regulatory mechanism of human mitochondrial NAD(P)+-dependent malate dehydrogenase (malic enzyme)
    Hui Chih Hung
    Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan, Republic of China
    Biochem J 392:39-45. 2005
    ..The Asp102 mutants, however, are much less sensitive to regulation by fumarate. Mutation of Asp102 leads to the desensitization of the co-operative effect between fumarate and substrates of the enzyme...
  90. ncbi IIAGlc inhibition of glycerol kinase: a communications network tunes protein motions at the allosteric site
    Peng Yu
    Department of Biochemistry and Biophysics and Texas Agricultural Experiment Station, Texas A and M University, College Station, Texas 77843 2128, USA
    Biochemistry 46:12355-65. 2007
    ..coli glycerol kinase suggest that motions of the allosteric site have an important role in the inhibition. Three E...
  91. ncbi Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators
    C A Stanley
    The Children s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, USA
    Diabetes 49:667-73. 2000
    ..Based on the three-dimensional structure of GDH, the mutations may function by impairing the binding of an inhibitory GTP to a domain responsible for the allosteric and cooperativity properties of GDH...
  92. ncbi An RNA-binding respiratory component mediates import of type II tRNAs into Leishmania mitochondria
    Saibal Chatterjee
    Genetic Engineering Laboratory, Indian Institute of Chemical Biology, Calcutta 700032, India
    J Biol Chem 281:25270-7. 2006
    ....
  93. ncbi A new allosteric site in glycogen phosphorylase b as a target for drug interactions
    N G Oikonomakos
    Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, Athens, 11635, Greece eie gr
    Structure 8:575-84. 2000
    ..Structural studies have been carried out in order to establish the mechanism of this unusual inhibitor...
  94. ncbi Human liver glycogen phosphorylase inhibitors bind at a new allosteric site
    V L Rath
    Department of Exploratory Medicinal Sciences, Global Research and Development, Pfizer Inc, Groton, CT 06340, USA
    Chem Biol 7:677-82. 2000
    ..Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target...
  95. pmc The 70-kDa heat shock protein chaperone nucleotide-binding domain in solution unveiled as a molecular machine that can reorient its functional subdomains
    Yongbo Zhang
    Biophysics Research Division and Departments of Biological Chemistry and Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 101:10272-7. 2004
    ..Our data suggest a hypothesis that cochaperone or substrate domain binding perturbs the relative subdomain orientations, thereby functionally and allosterically coupling to the nucleotide state of the NBD...
  96. pmc Discovery of an allosteric site in the caspases
    Jeanne A Hardy
    Sunesis Pharmaceuticals, Inc, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA
    Proc Natl Acad Sci U S A 101:12461-6. 2004
    ..We discovered a previously unreported and conserved allosteric site in a deep cavity at the dimer interface 14 A from the active site...
  97. ncbi The modular logic of signaling proteins: building allosteric switches from simple binding domains
    Wendell A Lim
    Department of Cellular and Molecular Pharmacology, Department of Biochemistry and Biophysics, University of California, San Francisco 94143 0450, USA
    Curr Opin Struct Biol 12:61-8. 2002
    ..A combination of structural, biophysical and computational studies is beginning to shed light on the fundamental principles governing this type of modular allostery...
  98. pmc Asymmetric and independent contribution of the second transmembrane segment 12' residues to diliganded gating of acetylcholine receptor channels: a single-channel study with choline as the agonist
    C Grosman
    Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, USA
    J Gen Physiol 115:637-51. 2000
    ....
  99. pmc Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme
    R Seppala
    1Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 1830, USA
    Am J Hum Genet 64:1563-9. 1999
    ..Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266...
  100. ncbi Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion
    Nobuyuki Ota
    Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143 2240, USA
    J Mol Biol 351:345-54. 2005
    ..Therefore, the ATD method should prove to be a powerful and general complement to experimental efforts to understand the physical basis of intramolecular signaling...
  101. ncbi Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1
    Kentaro Morita
    Graduate School of Frontier Biosciences, Osaka University, Osaka 565 0871, Japan
    Biochem Pharmacol 71:98-107. 2005
    ..The data indicate that the RXR heterodimers of NGFI-B and Nurr1 are selectively activated by the RXR ligand HX600, and that compounds such as HX600 will be valuable tools in investigating NGFI-B and Nurr1 function...

Research Grants63

  1. Novel lead molecule optimization targeting nicotinic receptor subtypes
    DENNIS BRIAN contact MCKAY; Fiscal Year: 2010
    ..was identified via molecular dynamics simulation and virtual screening using our computational model of the allosteric site on human 42 nAChRs, thus validating our model and supporting our proposed approaches...
  2. ALLOSTERIC SITE STRUCTURES OF CARDIOVASCULAR CHANNELS
    Arthur Karlin; Fiscal Year: 2011
    ..The results will provide insights into the molecular mechanisms of allosteric interactions in these two channels and will provide molecular structural bases for cardiovascular therapeutics targeted at these channels. ..
  3. Caspase-6 allosteric inhibitors: activity probes and neurodegeneration treatment
    JEANNE ANN HARDY; Fiscal Year: 2013
    ..This screen makes use of a recently discovered allosteric site in caspase-6 that is not present in any other caspase...
  4. Molecular Mechanism of Allosteric Modulation of the Oxytocin Receptor by Sterols
    VADIM GENNADYEVICH CHEREZOV; Fiscal Year: 2013
    ..hypothesis of this proposal is that cholesterol modulates the activity of the OXTR by binding to a distinct allosteric site(s) thus inducing a change in the receptor conformation...
  5. Cheminformatics of Allosteric mGluR Modulation promotes Therapeutic Development
    Jens Meiler; Fiscal Year: 2013
    ..activity of mGluR5 potentiators observed in this HTS can be used to generate a pharmacophore of the mGluR5 allosteric site. This map of steric and electronic features necessary for optimal interaction of modulators with mGluR5 will ..
  6. HTS to identify small molecules that disrupt Rab GTPase activator and effector pr
    Angela Wandinger Ness; Fiscal Year: 2009
    ..of small molecules that non-selectively activates GTP-binding on small Ras-like GTPases by binding to an allosteric site. New classes of inhibitors were found that are Rho family selective and Cdc42 specific and likely act ..
  7. Structure and Function of Carboxypeptidases
    Randal A Skidgel; Fiscal Year: 2013
    ..Hypothesis: CPM enhances B1R function by binding to an allosteric site and substrate binding by CPM results in B1R conformational change and enhanced receptor activation...
  8. Dimerization mechanisms of two procaspase subfamilies
    ALLAN CLAY CLARK; Fiscal Year: 2012
    ..Furthermore, we suggest that an allosteric site in the dimer interface affects the conformational switch between the two forms and couples dimerization to ..
  9. Optimization of Allosteric Modulators of 5-HT2C Receptor
    Jia Zhou; Fiscal Year: 2013
    ..easier to achieve high receptor subtype selectivity or even absolute specificity with a ligand binding to the allosteric site than with orthosteric ligands that bind to the endogenous ligand binding site...
  10. Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus Aureus
    Shahriar Mobashery; Fiscal Year: 2013
    ..We have elucidated an allosteric site on this protein that is triggered to facilitate opening of the active site for the physiological role of the ..
  11. Discovery and Development of Novel Glucose Dependent Partial Glucokinase Activato
    Duncan McRee; Fiscal Year: 2010
    ..of human GK 9hGK) ternary complexes (hGK:glucose:GKA) using either full or partial GKAs bound to the allosteric site and glucose bound to the active site...
  12. Conservation of allosteric mechanisms within an enzyme family
    ADAM STEEVES; Fiscal Year: 2012
    ..Establishing a detailed mechanistic picture of how the information from the allosteric site is transmitted to the active site will inform efforts to modulate the activity of the ubiquitin-proteasome ..
  13. Ca2+/CaM-Dependent Protein Kinase II: A Novel Target in Osteosarcoma
    Howard Schulman; Fiscal Year: 2012
    ..medicinal chemistry and preclinical development to generate improved CaMKII inhibitors that incorporate an allosteric site interaction...
  14. Structural biochemistry studies on MAP kinase allosteric binding sites
    JOHN JEFFERSON PERRY; Fiscal Year: 2013
    ..In Specific Aim 1, key functional interactions of the known 'D-motif'allosteric site, which is bound by certain substrates and regulatory enzymes, will be defined in p381...
  15. Studying how a general allosteric site regulates protein kinase function
    TERRY JUSTIN RETTENMAIER; Fiscal Year: 2013
    ..The long-term goal of this proposal is to determine how a general allosteric site regulates the substrate specificity and subcellular localization of the protein kinases...
  16. ALLOSTERIC ENHANCEMENT OF ADENOSINE RECEPTORS
    Joel M Linden; Fiscal Year: 2009
    ..These compounds bind to an allosteric site on the receptor to increase the affinity of adenosine to the orthosteric site on the A^R...
  17. Target-specific inhibition and activation of engineered protein tyrosine phosphat
    Anthony C Bishop; Fiscal Year: 2012
    ..family (Specific Aim 2: Target-specific activation of the NT4 family of PTPs);inhibiting PTPs by targeting an allosteric site that is 20[unreadable] removed from the conserved active site (Specific Aim 3: Targeting a PTP allosteric-..
  18. Control of Executioner Caspases with an Allosteric Switch
    JEANNE ANN HARDY; Fiscal Year: 2012
    ..When the small molecule effector we have selected or designed against binds to the evolved allosteric site, caspase activity will be inhibited...
  19. Secretin Receptor Structure, Function and Regulation
    Laurence J Miller; Fiscal Year: 2013
    ..detailed structural determinants for orthosteric agonists and antagonists, as well as to define the possible allosteric site of action of the endogenous agonist sequence within the receptor amino terminus...
  20. Molecular Mechanism of Flexible Carbohydrate-Protein Interaction in CD44
    Olgun Guvench; Fiscal Year: 2011
    ..the binding site, a large protein:carbohydrate binding interface, and an order-to-disorder transition at an allosteric site are all factors that complicate attempts to understand binding at an atomic level of detail...
  21. Structural Investigation of Allosteric Regulation in Bacterial Carbonic Anhydrase
    JEFF CRONK; Fiscal Year: 2007
    ..In view of its potential as a site for therapeutic intervention, the characterization of the allosteric site will be furthered by a virtual screen for potential non-substrate ligands...
  22. Functional effects of mGluR potentiators in the CNS
    P Jeffrey Conn; Fiscal Year: 2010
    ..These compounds do not activate mGlu2 directly but act at an allosteric site to potentiate glutamate-induced activation of the receptor...
  23. The Mevalonate Pathway in Streptococcus
    Thomas S Leyh; Fiscal Year: 2010
    ..The mevalonate pathway is essential for survival of the organism in mouse lung. DPM and the allosteric site offer a lead compound and target that provide an opportunity to develop a new class of antibiotics that could ..
  24. Identifying allosteric inhibitors of caspases
    Justin Scheer; Fiscal Year: 2005
    ..of allosteric inhibition in caspase-1, and 3) identify natural regulators of caspases acting through the allosteric site. The studies are to include both caspase-1 and caspase-3...
  25. GENETICS OF PHOSPHOFRUCTOKINASE STRUCTURE AND FUNCTION
    Simon Chang; Fiscal Year: 1993
    ..Moreover, the residues involve din the F2,6BP allosteric site will be investigated using certain mutant of RMPFK...
  26. Kinetic Studies of Transcription Elongation
    DOROTHY ERIE; Fiscal Year: 2005
    ..with the transition from the slow to the fast state being induced by binding of the templated NTP to the allosteric site. We hypothesize that this conformational switch is paramount to the regulation of transcription elongation ..
  27. Control of PP1/PP2A Activity With Small Molecule Toxins
    A Chamberlin; Fiscal Year: 2007
    ..the active sites of PP1 and PP2A, in the past several years some attention has shifted to characterizing an allosteric site on these phosphatases that modulates activity by interacting with a variety of binding (regulatory) proteins...
  28. HER-2/neu T Helper/Memory Vaccine for Breast Cancer
    Robert Humphreys; Fiscal Year: 2003
    Antigen Express scientists have demonstrated that the li-Key segment of the li protein, acting at an allosteric site of Class II molecules, facilitates charging by suitable vaccine peptides at the antigenic peptide-binding site...
  29. HIV li-Key/Peptide Vaccine
    Minzhen Xu; Fiscal Year: 2002
    ..Antigen Express scientists have discovered that a segment of the Ii protein called Ii-Key, which acts at an allosteric site on one end of the antigenic peptide binding site on MHC Class II molecules, greatly enhances the binding of a ..
  30. Targeting Allosteric Studies to Modulate Protein Interactions and Function
    Charles Craik; Fiscal Year: 2009
    ..lt;microM), and will be characterized in terms of their binding sites (active site, dimer interface, or allosteric site) for subsequent development. Collaborations are in place to provide libraries that are biased for success...
  31. Molecular Control of cGMP Signaling by PKGs and PDEs
    Jackie Corbin; Fiscal Year: 2007
    ..A thorough physical and biochemical characterization of PDE11 will be carded out, and the likelihood of regulation of this enzyme by ligand binding to its GAF domains or by enzyme phosphorylation will be explored. ..
  32. NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY
    OSMOND D CRUZ; Fiscal Year: 2001
    ..The preclinical data on in vivo efficacies of WHI-05 and WHI-07 will be essential to further explore the utility of these novel drugs for clinical studies in human patients. ..
  33. FLP-102: Rationally Engineered Antiviral Protein
    OSMOND D CRUZ; Fiscal Year: 2003
    ..The preclinical data on FLP-102 will be essential to further explore the utility of this novel recombinant PAP mutant for Phase II. ..
  34. PHI 346: A Novel Dual-Function Microbicide
    OSMOND D CRUZ; Fiscal Year: 2003
    ..Following successful completion of the Phase I in vivo efficacy studies, gel formulation of PHI-346 will be further explored as a vaginal dual-function microbicide in Phase II. ..
  35. METVAN: A Novel Anticancer Agent
    OSMOND D CRUZ; Fiscal Year: 2003
    ..The knowledge gained from these studies described under Specific Aims 1-2 is expected to facilitate the design of innovative treatment regimens employing METVAN for metastatic breast cancer and brain tumor patients. ..
  36. PHI-443: Novel Non-Spermicidal Anti-HIV Microbicide
    OSMOND D CRUZ; Fiscal Year: 2003
    ..Specific Aims 1 and 2 may provide the foundation for the clinical development of PHI-443 in Phase II studies as a safe, effective broad-spectrum anti-HIV microbicide without conception-inhibiting functions. ..
  37. Molecular Mechanisms of PDE5 Regulation
    Jackie Corbin; Fiscal Year: 2005
    ..Results of these studies will provide a basis for understanding fundamental questions relating to cGMP signaling in many tissues. ..
  38. Phase II SBIR: WHI-07: A Novel Dual-Function Microbicide
    OSMOND D CRUZ; Fiscal Year: 2005
    ....
  39. Stampidine: A Novel Broad-Spectrum Anti-HIV Microbicide
    OSMOND D CRUZ; Fiscal Year: 2005
    ..Specific Aims 1 and 2 may provide the foundation for the clinical development of STAMP in Phase II studies as a safe, effective broad-spectrum anti-HIV microbicide without conception-inhibiting functions. ..
  40. Vanadocenes as a New Class of Spermicidal Drugs
    OSMOND D CRUZ; Fiscal Year: 2007
    ..unreadable] [unreadable] [unreadable]..
  41. Ultrafast Time-Resolved Crystallography on Scapharca Hb
    WILLIAM ROYER; Fiscal Year: 2007
    ..Understanding such principles will aid in the rational manipulation of a number of biological processes. ..
  42. Molecular Modulators of HCV Replication
    Neerja Kaushik Basu; Fiscal Year: 2007
    ..This will enable us to understand, at the molecular level, the replication process of hepatitis C virus and will further facilitate the development of effective drugs/inhibitors against HCV. ..
  43. EFFECTORS AND IINHIBITORS OF SARS VIRUS POLYMERASE
    Neerja Kaushik Basu; Fiscal Year: 2006
    ..Further, analysis of the sensitivity of the SARS-CoV RdRp towards a panel of known and novel inhibitors of polymerases will provide new leads in the quest for specific antiviral agents against the SARS-CoV RdRp. ..
  44. STRUCTURAL BASIS FOR ASSEMBLY OF COOPERATIVE HEMOGLOBINS
    WILLIAM ROYER; Fiscal Year: 2005
    ..Our structural analysis suggests a number of hypotheses for the regulation of function, which we will be testing by mutagenesis, kinetic and structural experiments. ..
  45. Glucose Signaling: Regulation of Enzyme Activity
    DONALD PETTIGREW; Fiscal Year: 2006
    ..coli. ..
  46. BIOCHEMISTRY OF HEPATITIS C VIRUS REPLICASE
    Neerja Kaushik Basu; Fiscal Year: 2003
    ..Aim 2: To elucidate the catalytic roles of specific amino acid residues in the polymerase function. Aim 3: To determine protein-protein interactions between HCV replicase and other nonstructural viral proteins. ..
  47. Structural basis of regulation of IRF
    WILLIAM ROYER; Fiscal Year: 2007
    ..These studies will provide insight into the molecular mechanism of IRF signaling, providing possible targets for rational drug design to combat viral pathogenesis. ..
  48. STRUCTURAL STUDIES OF PROTEIN SUBUNITS
    Thomas Smith; Fiscal Year: 2004
    ..These studies have the potential of changing the way we view the early steps in the viral infection process and will allow us to develop tools that are applicable to other viral systems. ..
  49. Molecular Biology of 5HT2A receptor expressing synapses
    Milt Teitler; Fiscal Year: 2005
    ....
  50. Rheb GTPase as chemotherapeutic target for brain tumors
    LAWRENCE QUILLIAM; Fiscal Year: 2009
    ..They will address the molecular basis of non-Ras action of FTIs and demonstrate the value of targeting Rheb in cancer therapy. ..
  51. Structural Studies of NAGS
    Dashuang Shi; Fiscal Year: 2006
    ..abstract_text> ..
  52. Mechanisms of Heat Activation and Multimodal Functions of VR1 Receptor Channels
    Feng Qin; Fiscal Year: 2010
    ....
  53. Ribonucleotide Reductase: A Cancer Chemotherapy Target
    BARRY COOPERMAN; Fiscal Year: 2005
    ..Such carriers, along with bivalent nucleosides, and phosphorylated bivalent nucleoside prodrugs, will permit in vivo testing of our compounds. ..
  54. Purchase of a Beckman XL-1 Analytical Ultracentrifuge
    Dorothy Beckett; Fiscal Year: 2002
    ..The versatility provided by the absorption and interference optics of the Beckman Optima XL-I analytical ultracentrifuge will be essential to the success of the broad range of applications described in this proposal. ..
  55. Towards Mechanistic Explanations of Striatal Disorders
    Elizabeth A Thomas; Fiscal Year: 2010
    ..ARRA Request: 2 R01 NS044169-06A2 Thomas, Elizabeth A. ..
  56. Mechanisms and Control of Urea Biosynthesis
    FRANK RAUSHEL; Fiscal Year: 2007
    ..abstract_text> ..
  57. Ped Endocrine Career Development in Diabetes Research
    Charles Stanley; Fiscal Year: 2007
    ..The Program is strongly supported by access to a superb range of institutional resources, including the CHOP GCRC and the UPenn DERC. Request is made for 2 Appointee slots in this Program each year. ..
  58. ALLOSTERIC REGULATION OF SUBSTRATE CHANNELING
    Michael Dunn; Fiscal Year: 2006
    ..abstract_text> ..
  59. Bacterial Cell Surfaces Gordon Conference
    Barry Rosen; Fiscal Year: 2004
    ..abstract_text> ..
  60. Mechanistic studies of DNA repair and damage response
    Dorothy A Erie; Fiscal Year: 2010
    ..abstract_text> ..
  61. MOLECULAR BASIS OF A NEW FORM OF HYPERINSULINISM
    CHARLES ALFRED STANLEY; Fiscal Year: 2010
    ....
  62. ISOTOPIC PROBES OF ENZYME REACTION MECHANISMS
    FRANK RAUSHEL; Fiscal Year: 2005
    ..These investigations will complement concurrent efforts to direct the evolution of new and enhanced activities from present-day proteins. ..
  63. Structure of Beta-lactam resistance regulators
    MARTIN SAFO; Fiscal Year: 2007
    ..Subsequently, the structures of the proteins will be determined using X-ray crystallography. [unreadable] [unreadable]..