- Structural Basis of allosteric regulation and substrate specificity of the non-phosphorylating glyceraldehyde 3-Phosphate dehydrogenase from Thermoproteus tenax
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...
- Surface sites for engineering allosteric control in proteins
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...
- 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...
- A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand
Drug Discovery Biology Laboratory, Monash University, 3800 Victoria, Australia
J Biol Chem 283:29312-21. 2008
- Allosteric modulation of G protein-coupled receptors: a pharmacological perspective
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...
- Allosteric disulfide bonds
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...
- Allostery is an intrinsic property of the protease domain of DegS: implications for enzyme function and evolution
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...
- Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor
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...
- The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors
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...
- 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...
- Allostery and cooperativity revisited
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...
- 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...
- Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach
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...
- Binding leverage as a molecular basis for allosteric regulation
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...
- 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
- Amide hydrogen exchange reveals conformational changes in hsp70 chaperones important for allosteric regulation
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...
- 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...
- A fluorescence resonance energy transfer-based M2 muscarinic receptor sensor reveals rapid kinetics of allosteric modulation
Institute of Pharmacology and Toxicology and the Rudolf Virchow Center, University of Wurzburg, 97078 Wurzburg, Germany
J Biol Chem 285:8793-800. 2010
- Allosteric vs. spontaneous exit-site (E-site) tRNA dissociation early in protein synthesis
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
- 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...
- Coherent conformational degrees of freedom as a structural basis for allosteric communication
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...
- Is allostery an intrinsic property of all dynamic proteins?
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...
- 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
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...
- 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...
- Phosphoenolpyruvate carboxylase: three-dimensional structure and molecular mechanisms
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...
- Impact of species variability and 'probe-dependence' on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor
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...
- The role of transmembrane domain 3 in the actions of orthosteric, allosteric, and atypical agonists of the M4 muscarinic acetylcholine receptor
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, 3052, Victoria, Australia
Mol Pharmacol 79:855-65. 2011
- Conopeptide ρ-TIA defines a new allosteric site on the extracellular surface of the α1B-adrenoceptor
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...
- 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
- Kinetic, mechanistic, and structural aspects of unliganded gating of acetylcholine receptor channels: a single-channel study of second transmembrane segment 12' mutants
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...
- Allosteric small molecules unveil a role of an extracellular E2/transmembrane helix 7 junction for G protein-coupled receptor activation
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...
- 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...
- 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...
- 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 ..
- 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...
- Allosteric modulation of Ras positions Q61 for a direct role in catalysis
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...
- Ionic contacts at DnaK substrate binding domain involved in the allosteric regulation of lid dynamics
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...
- 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
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...
- Dynamic allostery in the methionine repressor revealed by force distribution analysis
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...
- The exploding field of the HCV polymerase non-nucleoside inhibitors: summary of a first generation compounds
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...
- 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...
- 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...
- Computational studies of LXR molecular interactions reveal an allosteric communication pathway
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...
- Interactions of orthosteric and allosteric ligands with [3H]dimethyl-W84 at the common allosteric site of muscarinic M2 receptors
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...
- 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...
- 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...
- Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor
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...
- Simulations of allosteric transitions
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...
- 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...
- 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 ..
- Structure of the large subunit of class Ib ribonucleotide reductase from Salmonella typhimurium and its complexes with allosteric effectors
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...
- Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression
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...
- 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...
- 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...
- A geometry-based generic predictor for catalytic and allosteric sites
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...
- A protein phosphorylation switch at the conserved allosteric site in GP
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 ..
- 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...
- 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) ..
- 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...
- 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...
- 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
- 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...
- Molecular design of artificial molecular and ion recognition systems with allosteric guest responses
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...
- 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...
- IIAGlc inhibition of glycerol kinase: a communications network tunes protein motions at the allosteric site
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...
- "Ping-pong" interactions between mitochondrial tRNA import receptors within a multiprotein complex
Subhendra Nath Bhattacharyya
Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Calcutta 700032, India
Mol Cell Biol 23:5217-24. 2003
..This "ping-pong" mechanism may be an effective means to maintain a balanced tRNA pool for mitochondrial translation...
- A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions
S J Edelstein
Departement de Biochimie, Universite de Geneve, Switzerland
Biol Cybern 75:361-79. 1996
..In terms of future developments, the analysis presented here provides a physical basis for constructing more biologically realistic models of synaptic modulation that may be applied to artificial neural networks...
- Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme
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...
- 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...
- 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
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, USA
J Gen Physiol 115:637-51. 2000
- The number of catalytic elements is crucial for the emergence of metabolic cores
Ildefonso M De La Fuente
Department of Mathematics, Faculty of Science and Technology, University of the Basque Country, Vizcaya, Spain
PLoS ONE 4:e7510. 2009
- A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo
Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH 4002 Basel, Switzerland
Proc Natl Acad Sci U S A 102:18712-7. 2005
..dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain...
- Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1
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...
- A glycine-dependent riboswitch that uses cooperative binding to control gene expression
Department of Molecular, Cellular, and Developmental Biology, Yale University, Post Office Box 208103, New Haven, CT 06520 8103, USA
Science 306:275-9. 2004
..Thus, riboswitches perform key regulatory roles and exhibit complex performance characteristics that previously had been observed only with protein factors...
- Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics
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...
- 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...
- Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site
Stefania Di Marco
Istituto di Ricerche di Biologia Molecolare P Angeletti, Pomezia Rome, Italy
J Biol Chem 280:29765-70. 2005
..Our structures identify a novel mechanism by which a new class of allosteric inhibitors inhibits the HCV polymerase and open the way to the development of novel antiviral agents against this clinically relevant human pathogen...
- The 70-kDa heat shock protein chaperone nucleotide-binding domain in solution unveiled as a molecular machine that can reorient its functional subdomains
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...
- Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion
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...
- Inhibition of the calcineurin-NFAT interaction by small organic molecules reflects binding at an allosteric site
CBR Institute for Biomedical Research, Boston, MA 02115, USA
J Biol Chem 280:37698-706. 2005
..The finding that an allosteric site controls NFAT binding opens new alternatives for inhibition of calcineurin-NFAT signaling.
- Thrombin: a paradigm for enzymes allosterically activated by monovalent cations
Enrico Di Cera
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110, USA
C R Biol 327:1065-76. 2004
..formation of a ternary intermediate with the enzyme-substrate complex, or binding of the cation to an allosteric site in the protein. Thrombin is a Na+-activated enzyme with procoagulant, anticoagulant and signaling roles...
- Residue Asp-189 controls both substrate binding and the monovalent cation specificity of thrombin
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri 63110, USA
J Biol Chem 279:10103-8. 2004
- Allosteric determinants in guanine nucleotide-binding proteins
Mark E Hatley
Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9050, USA
Proc Natl Acad Sci U S A 100:14445-50. 2003
..The network of residues identified by the SCA appears to comprise a core allosteric mechanism conferring nucleotide-dependent switching; the specific features of different G protein family members are built on this core...
- An RNA-binding respiratory component mediates import of type II tRNAs into Leishmania mitochondria
Genetic Engineering Laboratory, Indian Institute of Chemical Biology, Calcutta 700032, India
J Biol Chem 281:25270-7. 2006
- A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators
Alice L Rodriguez
Department of Pharmacology and Program in Translational Neuropharmacology, Vanderbilt University Medical Center, 23rd Ave South at Pierce, 417 D Preston Research Bldg, Nashville, Tennessee 37232 6600, USA
Mol Pharmacol 68:1793-802. 2005
..The third compound, 5-methyl-6-(phenylethynyl)-pyridine (5MPEP), acts as a neutral allosteric site ligand that binds to the MPEP site and has no effects alone...
- Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition
Canadian Institutes for Health Research Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
J Biol Chem 278:9489-95. 2003
..The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase...
- Quantitative analysis of DNA binding by the Escherichia coli arginine repressor
Chemistry Department, Princeton University, Princeton, NJ 08544 1009, USA
J Mol Biol 312:949-62. 2001
..The results indicate that subunit assembly plays no role in activation, although communication among subunits of the ArgR hexamer is required for specific DNA binding. The data suggest that DNA is also an allosteric effector of ArgR...
- Manipulation of ligand binding affinity by exploitation of conformational coupling
J S Marvin
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA
Nat Struct Biol 8:795-8. 2001
..A family of 20 variants was generated with affinities ranging from an approximately 100-fold improvement (7.4 nM) to an approximately two-fold weakening (1.8 mM) relative to the wild type protein (800 nM)...
- Allosteric site variants of Haemophilus influenzae beta-carbonic anhydrase
Roger S Rowlett
Department of Chemistry, Colgate University, 13 Oak Drive, Hamilton, New York 13346, USA
Biochemistry 48:6146-56. 2009
..These results lend additional support to the hypothesis that HICA is an allosteric enzyme that can adopt active and inactive conformations, the latter of which is stabilized by bicarbonate ion binding to a non-catalytic site...
- G protein-coupled receptor allosterism and complexing
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...
- Allosteric networks governing regulation and catalysis of Src-family protein tyrosine kinases: implications for disease-associated kinases
Heung Chin Cheng
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
Clin Exp Pharmacol Physiol 37:93-101. 2010
..4. Further investigations to decipher the roles of the hydrophobic spine residues in regulation and catalysis of SFKs will benefit the development of therapeutic SFK inhibitors for cancer treatment...
- Contact rearrangements form coupled networks from local motions in allosteric proteins
Michael D Daily
Program in Molecular and Computational Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA
Proteins 71:455-66. 2008
..In summary, residue-residue contact rearrangement networks provide useful representations of the portions of allosteric pathways resulting from coupled local motions...
- MHC class II allosteric site drugs: new immunotherapeutics for malignant, infectious and autoimmune diseases
Antigen Express, Inc, One Innovation Drive, Worcester, MA 01605, USA
Scand J Immunol 54:39-44. 2001
..of the 'Ii-Key' segment of the Ii protein with the major histocmpatibility complex (MHC) Class II allosteric site, which is adjacent to the antigenic peptide-binding site, creates therapeutic opportunities by regulating the ..
- Cellular activation of leukocyte function-associated antigen-1 and its affinity are regulated at the I domain allosteric site
M L Lupher
ICOS Corporation, 22021 20th Avenue SE, Bothell, WA 98021, USA
J Immunol 167:1431-9. 2001
..Binding of the LFA-1 ligand, ICAM-1 to the metal ion-dependent adhesion site is regulated by the I domain allosteric site (IDAS)...
- Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations
Division of Endocrinology, The Children s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA
Biochem J 363:81-7. 2002
- 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...
- Nicotinic receptors, allosteric proteins and medicine
Jean Pierre Changeux
Research Unit, National Center of Scientific Research 2182, Department of Neuroscience, Pasteur Institute, Paris, France
Trends Mol Med 14:93-102. 2008
- The structure of apo human glutamate dehydrogenase details subunit communication and allostery
Thomas J Smith
Donald Danforth Plant Science Center, 975 North Warson Road, St Louis, MO 63132, USA
J Mol Biol 318:765-77. 2002
..These results support the previous proposal that purines regulate GDH activity by altering the dynamics of the NAD binding domain. Finally, a possible structural mechanism for negative cooperativity is presented...
- FimH forms catch bonds that are enhanced by mechanical force due to allosteric regulation
Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA
J Biol Chem 283:11596-605. 2008
..Additionally, these observations may provide a means for designing antiadhesive mechanisms...
- Local motions in a benchmark of allosteric proteins
Michael D Daily
Program in Molecular and Computational Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA
Proteins 67:385-99. 2007
..However, allosteric proteins exhibit twice as much percent motion on average as nonallosteric proteins with ligand-induced motion. These observations may guide efforts to design flexibility and allostery into proteins...
- 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...