allosteric regulation


Summary: The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES.

Top Publications

  1. Magnaghi P, D Alessio R, Valsasina B, Avanzi N, Rizzi S, Asa D, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol. 2013;9:548-56 pubmed publisher
    ..The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target. ..
  2. Das R, Liang Y, Mariano J, Li J, Huang T, King A, et al. Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine. EMBO J. 2013;32:2504-16 pubmed publisher
    ..Thus, gp78 is a ubiquitination machine where multiple E2-binding sites coordinately facilitate processive ubiquitination. ..
  3. Jiménez Osés G, Osuna S, Gao X, Sawaya M, Gilson L, Collier S, et al. The role of distant mutations and allosteric regulation on LovD active site dynamics. Nat Chem Biol. 2014;10:431-6 pubmed publisher
    ..Mutations markedly altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF. ..
  4. Besprozvannaya M, Pivorunas V, Feldman Z, Burton B. SpoIIIE protein achieves directional DNA translocation through allosteric regulation of ATPase activity by an accessory domain. J Biol Chem. 2013;288:28962-74 pubmed publisher
    ..Together, our data reveal that directional activation involves allosteric regulation of ATP turnover through coordinated action of ? domains...
  5. Blacklock K, Verkhivker G. Experimentally guided structural modeling and dynamics analysis of Hsp90-p53 interactions: allosteric regulation of the Hsp90 chaperone by a client protein. J Chem Inf Model. 2013;53:2962-78 pubmed publisher
    ..In this work, we have probed mechanistic aspects of allosteric regulation of Hsp90 by client proteins via a detailed computational study of Hsp90 interactions with the tumor ..
  6. Mahmoud M, Ali H, Ahn K, Damaraju A, Samala S, Pulipati V, et al. Structure-activity relationship study of indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1). J Med Chem. 2013;56:7965-75 pubmed publisher
    ..It showed an equilibrium dissociation constant (KB) of 167.3 nM with a markedly high binding cooperativity factor (? = 16.55) and potent antagonism of agonist-induced GTP?S binding. ..
  7. Paramo T, Piggot T, Bryant C, Bond P. The structural basis for endotoxin-induced allosteric regulation of the Toll-like receptor 4 (TLR4) innate immune receptor. J Biol Chem. 2013;288:36215-25 pubmed publisher
    ..Remarkably, within the receptor complex, we observe spontaneous transitions between active and inactive signaling states of Phe-126, and we confirm that Phe-126 is indeed the "molecular switch" in endotoxic signaling. ..
  8. Revsbech I, Tufts D, Projecto Garcia J, Moriyama H, Weber R, Storz J, et al. Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges. J Exp Biol. 2013;216:4264-71 pubmed publisher
  9. Gustavsson M, Verardi R, Mullen D, Mote K, Traaseth N, Gopinath T, et al. Allosteric regulation of SERCA by phosphorylation-mediated conformational shift of phospholamban. Proc Natl Acad Sci U S A. 2013;110:17338-43 pubmed publisher
    ..We found that the allosteric regulation of SERCA depends on the conformational equilibrium of PLN, whose cytoplasmic regulatory domain ..

Scientific Experts

More Information


  1. Gowans G, Hawley S, Ross F, Hardie D. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013;18:556-66 pubmed publisher
    ..Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism.
  2. Rodgers T, Townsend P, Burnell D, Jones M, Richards S, McLeish T, et al. Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors. PLoS Biol. 2013;11:e1001651 pubmed publisher
  3. Gustavsson A, van Niekerk D, Adiels C, Kooi B, Goksör M, Snoep J. Allosteric regulation of phosphofructokinase controls the emergence of glycolytic oscillations in isolated yeast cells. FEBS J. 2014;281:2784-93 pubmed publisher [Database section added 14 May 2014 after original online publication]. ..
  4. Palazzesi F, Barducci A, Tollinger M, Parrinello M. The allosteric communication pathways in KIX domain of CBP. Proc Natl Acad Sci U S A. 2013;110:14237-42 pubmed publisher
    b>Allosteric regulation plays an important role in a myriad of biomacromolecular processes. Specifically, in a protein, the process of allostery refers to the transmission of a local perturbation, such as ligand binding, to a distant site...
  5. Lyumkis D, Talley H, Stewart A, Shah S, Park C, Tama F, et al. Allosteric regulation of DNA cleavage and sequence-specificity through run-on oligomerization. Structure. 2013;21:1848-58 pubmed publisher
    ..The hybrid approach reveals an unusual mechanism of enzyme activation that explains SgrAI's oligomerization and allosteric behavior. ..
  6. Steffen J, Tholey R, Langelier M, Planck J, Schiewer M, Lal S, et al. Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer. Cancer Res. 2014;74:31-7 pubmed publisher
    ..Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1...
  7. Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, et al. ASD v2.0: updated content and novel features focusing on allosteric regulation. Nucleic Acids Res. 2014;42:D510-6 pubmed publisher
    ..Owing to the inherent high receptor selectivity and lower target-based toxicity, allosteric regulation is expected to assume a more prominent role in drug discovery and bioengineering, leading to the rapid ..
  8. Motlagh H, Wrabl J, Li J, Hilser V. The ensemble nature of allostery. Nature. 2014;508:331-9 pubmed publisher
    ..Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems. ..
  9. Costa T, dos Reis F, Lima A. Substrate inhibition and allosteric regulation by heparan sulfate of Trypanosoma brucei cathepsin L. Biochim Biophys Acta. 2012;1824:493-501 pubmed publisher
    ..We propose that brucipain shifts between an active and an inactive form as a result of temperature-dependent allosteric regulation.
  10. Umair S, Knight J, Patchett M, Bland R, Simpson H. Nucleotide allosteric regulation of the glutamate dehydrogenases of Teladorsagia circumcincta and Haemonchus contortus. Comp Biochem Physiol B Biochem Mol Biol. 2012;161:255-60 pubmed publisher
    ..GDH provides a pathway for ammonia assimilation, although the affinity for ammonia was low. Allosteric regulation by GTP, ATP and ADP of L3 and adult H...
  11. Motlagh H, Hilser V. Agonism/antagonism switching in allosteric ensembles. Proc Natl Acad Sci U S A. 2012;109:4134-9 pubmed publisher
  12. Yang J, Seo S, Jang S, Jung G, Kim S. Rational engineering of enzyme allosteric regulation through sequence evolution analysis. PLoS Comput Biol. 2012;8:e1002612 pubmed publisher
    Control of enzyme allosteric regulation is required to drive metabolic flux toward desired levels...
  13. Burendahl S, Nilsson L. Computational studies of LXR molecular interactions reveal an allosteric communication pathway. Proteins. 2012;80:294-306 pubmed publisher
    ..Thus, additional specificity between LXR? and its cofactors is likely to be found in molecular interactions outside the cofactor peptide or in other biological factors. ..
  14. Garriga D, Ferrer Orta C, Querol Audi J, Oliva B, Verdaguer N. Role of motif B loop in allosteric regulation of RNA-dependent RNA polymerization activity. J Mol Biol. 2013;425:2279-87 pubmed publisher
    ..Among all movements observed, motif B, and the B-loop at its N-terminus in particular, appears as a new potential druggable site. ..
  15. Palmieri L, Rastelli G. ?C helix displacement as a general approach for allosteric modulation of protein kinases. Drug Discov Today. 2013;18:407-14 pubmed publisher
    ..A structure-based survey of the allosteric regulation of ?C helix conformation in various kinase families is provided, highlighting key allosteric pockets and ..
  16. Callahan P, Hutchings E, Kille N, Chapman J, Terry A. Positive allosteric modulator of ?7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Neuropharmacology. 2013;67:201-12 pubmed publisher
    ..g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age. ..
  17. Jaffe E. Impact of quaternary structure dynamics on allosteric drug discovery. Curr Top Med Chem. 2013;13:55-63 pubmed
    The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation ..
  18. Prasannan C, Villar M, Artigues A, Fenton A. Identification of regions of rabbit muscle pyruvate kinase important for allosteric regulation by phenylalanine, detected by H/D exchange mass spectrometry. Biochemistry. 2013;52:1998-2006 pubmed publisher
    ..e., those changes common upon the addition of alanine vs phenylalanine) from changes associated with allosteric regulation (i.e., those elicited by the addition of phenylalanine binding, but not alanine binding)...
  19. Gui D, Lewis C, Vander Heiden M. Allosteric regulation of PKM2 allows cellular adaptation to different physiological states. Sci Signal. 2013;6:pe7 pubmed publisher
    Pyruvate kinase isoform M2 (PKM2) activity is subject to complex allosteric regulation. Recently, serine and SAICAR (succinylaminoimidazolecarboxamide ribose-5'-phosphate) were identified as previously unrecognized ..
  20. Nussinov R, Tsai C, Ma B. The underappreciated role of allostery in the cellular network. Annu Rev Biophys. 2013;42:169-89 pubmed publisher
    ..The challenges are colossal; the inspiring reward will be predicting function, misfunction, and outcomes of drug regimes. ..
  21. Crick F, Wyman J. A footnote on allostery. J Mol Biol. 2013;425:1500-8 pubmed publisher
    ..The text also developed the concept of the allosteric range and included a simple equation for calculation of the Hill coefficient from the parameters of the Monod-Wyman-Changeux model. ..
  22. Yonetani T, Kanaori K. How does hemoglobin generate such diverse functionality of physiological relevance?. Biochim Biophys Acta. 2013;1834:1873-84 pubmed publisher
    ..This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. ..
  23. Sidhu P, Abdel Aziz M, Sarkar A, Mehta A, Zhou Q, Desai U. Designing allosteric regulators of thrombin. Exosite 2 features multiple subsites that can be targeted by sulfated small molecules for inducing inhibition. J Med Chem. 2013;56:5059-70 pubmed publisher
    ..The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition. ..
  24. Berezovsky I. Thermodynamics of allostery paves a way to allosteric drugs. Biochim Biophys Acta. 2013;1834:830-5 pubmed publisher
    We overview here our recent work on the thermodynamic view of allosteric regulation and communication...
  25. Loweth J, Tseng K, Wolf M. Using metabotropic glutamate receptors to modulate cocaine's synaptic and behavioral effects: mGluR1 finds a niche. Curr Opin Neurobiol. 2013;23:500-6 pubmed publisher
    ..Therefore, activation of mGluR1 with positive allosteric modulators (PAM) may reduce cue-induced relapse in abstinent cocaine addicts. ..
  26. Reynolds K, McLaughlin R, Ranganathan R. Hot spots for allosteric regulation on protein surfaces. Cell. 2011;147:1564-75 pubmed publisher
    ..These findings suggest that sectors enable the evolution of intermolecular communication and regulation. ..
  27. Denisov I, Sligar S. A novel type of allosteric regulation: functional cooperativity in monomeric proteins. Arch Biochem Biophys. 2012;519:91-102 pubmed publisher
    Cooperative functional properties and allosteric regulation in cytochromes P450 play an important role in xenobiotic metabolism and define one of the main mechanisms of drug-drug interactions...
  28. Zhang P, Smith Nguyen E, Keshwani M, Deal M, Kornev A, Taylor S. Structure and allostery of the PKA RII? tetrameric holoenzyme. Science. 2012;335:712-6 pubmed publisher
    ..The quaternary structure of the RII? tetramer differs appreciably from our model of the RI? tetramer, confirming the small-angle x-ray scattering prediction that the structures of each PKA tetramer are different. ..
  29. Nussinov R, Tsai C, Xin F, Radivojac P. Allosteric post-translational modification codes. Trends Biochem Sci. 2012;37:447-55 pubmed publisher
    ..From an evolutionary standpoint, harnessing this immense, yet highly specific, PTM code is an extremely efficient vehicle that can save a cell several-fold in gene number and speed up its response to environmental change. ..
  30. Osorio Paz I, Sánchez Chávez G, Salceda R. Control of glycogen content in retina: allosteric regulation of glycogen synthase. PLoS ONE. 2012;7:e30822 pubmed publisher
    ..Therefore, under hypoglycemic situations retina energy supply is strongly compromised and could lead to the alterations observed in type 1 diabetes. ..
  31. Uteshev V. ?7 nicotinic ACh receptors as a ligand-gated source of Ca(2+) ions: the search for a Ca(2+) optimum. Adv Exp Med Biol. 2012;740:603-38 pubmed publisher
    ..In this review, the focus is placed on ?7 nAChR-mediated currents and Ca(2+) influx and how this source of Ca(2+) entry compares to NMDA receptors in supporting cytosolic Ca(2+) homeostasis, neuronal function and survival. ..
  32. Masterson L, Cembran A, Shi L, Veglia G. Allostery and binding cooperativity of the catalytic subunit of protein kinase A by NMR spectroscopy and molecular dynamics simulations. Adv Protein Chem Struct Biol. 2012;87:363-89 pubmed publisher
    ..These studies support a central role of conformational dynamics in many aspects of enzymatic turnover and suggest future avenues for controlling enzymatic function. ..
  33. Canals M, Lane J, Wen A, Scammells P, Sexton P, Christopoulos A. A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation. J Biol Chem. 2012;287:650-9 pubmed publisher
    ..These findings define a chemical biological framework that can be applied to the study and classification of allosteric modulators across different GPCR families. ..
  34. McLean S, Idris N, Grayson B, Gendle D, Mackie C, Lesage A, et al. PNU-120596, a positive allosteric modulator of ?7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats. J Psychopharmacol. 2012;26:1265-70 pubmed publisher
    ..001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of ?7 nACh receptors. ..
  35. Krimm I, Lancelin J, Praly J. Binding evaluation of fragment-based scaffolds for probing allosteric enzymes. J Med Chem. 2012;55:1287-95 pubmed publisher
    ..The work we report illustrates the power of fragmentlike ligands not only for probing the various binding pockets of proteins, but also for uncovering cooperativity between these various binding sites. ..
  36. Kalodimos C. Protein function and allostery: a dynamic relationship. Ann N Y Acad Sci. 2012;1260:81-6 pubmed publisher
    Allostery is a fundamental process by which distant sites within a protein system sense each other. Allosteric regulation is such an efficient mechanism that it is used to control protein activity in most biological processes, including ..
  37. Oakhill J, Scott J, Kemp B. AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab. 2012;23:125-32 pubmed publisher
    ..Here we discuss the current state of AMPK regulation by adenine nucleotides and we propose that AMPK functions as an adenylate charge-regulated protein kinase. ..
  38. Piscitelli F, Ligresti A, La Regina G, Coluccia A, Morera L, Allarà M, et al. Indole-2-carboxamides as allosteric modulators of the cannabinoid CB? receptor. J Med Chem. 2012;55:5627-31 pubmed publisher
  39. Hilser V, Wrabl J, Motlagh H. Structural and energetic basis of allostery. Annu Rev Biophys. 2012;41:585-609 pubmed publisher
    ..The ensemble view of allostery that emerges provides insights into the energetic prerequisites of site-to-site coupling and thus into how allostery works. ..
  40. Bhagwanth S, Mishra S, Daya R, Mah J, Mishra R, Johnson R. Transformation of Pro-Leu-Gly-NH2 peptidomimetic positive allosteric modulators of the dopamine D2 receptor into negative modulators. ACS Chem Neurosci. 2012;3:274-84 pubmed publisher
    ..This hypothesis was shown to be correct as 3a and 4a where found to be negative allosteric modulators, whereas their unmethylated derivatives were positive allosteric modulators of the dopamine D(2) receptor. ..
  41. Nussinov R, Tsai C. Allostery in disease and in drug discovery. Cell. 2013;153:293-305 pubmed publisher
    ..We aim to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level and to emphasize the potential of allosteric drugs in innovative therapies...
  42. Wang C, Lewis R. Emerging opportunities for allosteric modulation of G-protein coupled receptors. Biochem Pharmacol. 2013;85:153-62 pubmed publisher
    ..This analysis has identified a new extracellular salt bridge (ESB-2) that might be exploited in the design of allosteric modulators. ..
  43. Wang Q, Zheng M, Huang Z, Liu X, Zhou H, Chen Y, et al. Toward understanding the molecular basis for chemical allosteric modulator design. J Mol Graph Model. 2012;38:324-33 pubmed publisher
    Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient...
  44. Baillie G, Horswill J, Anavi Goffer S, Reggio P, Bolognini D, Abood M, et al. CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity. Mol Pharmacol. 2013;83:322-38 pubmed publisher
    ..The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway. ..
  45. Polucci P, Magnaghi P, Angiolini M, Asa D, Avanzi N, Badari A, et al. Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. J Med Chem. 2013;56:437-50 pubmed publisher
    ..This represents a first step toward a new class of potential anticancer agents. ..
  46. Bidon Chanal A, Fuertes A, Alonso D, Perez D, Martinez A, Luque F, et al. Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin. Eur J Med Chem. 2013;60:479-89 pubmed publisher
    ..The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action. ..
  47. Chen L, Wang J, Zhang Y, Yan S, Neumann D, Schlattner U, et al. AMP-activated protein kinase undergoes nucleotide-dependent conformational changes. Nat Struct Mol Biol. 2012;19:716-8 pubmed publisher
    ..However, site 3 is occupied in the presence of AMP. Mutagenesis studies indicate that sites 3 and 4 are important for AMPK allosteric activation. ..
  48. Liu W, Chun E, Thompson A, Chubukov P, Xu F, KATRITCH V, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012;337:232-6 pubmed publisher
    ..These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function. ..
  49. Choi J, Seo M, Kyeong H, Kim E, Kim H. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc Natl Acad Sci U S A. 2013;110:10171-6 pubmed publisher
    ..Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear...
  50. Edelstein S, Le Novère N. Cooperativity of allosteric receptors. J Mol Biol. 2013;425:1424-32 pubmed publisher
    ..The concepts of equivalent monomer and allosteric range were originally proposed in 1965 by Crick and Wyman in a manuscript circulated among the proponents of allostery, but only now published for the first time in this special issue. ..
  51. Selwood T, Jaffe E. Dynamic dissociating homo-oligomers and the control of protein function. Arch Biochem Biophys. 2012;519:131-43 pubmed publisher
    ..equilibria through the 20th and into the 21st centuries and the relationship of these equilibria to allosteric regulation by the non-covalent binding of ligands...
  52. Schelshorn D, Joly F, Mutel S, Hampe C, Breton B, Mutel V, et al. Lateral allosterism in the glucagon receptor family: glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation. Mol Pharmacol. 2012;81:309-18 pubmed publisher
    ..with respect to GLP-1-induced ?-arrestin recruitment and calcium flux, which suggests a form of allosteric regulation between the receptors...
  53. Suetsugu S. Activation of nucleation promoting factors for directional actin filament elongation: allosteric regulation and multimerization on the membrane. Semin Cell Dev Biol. 2013;24:267-71 pubmed publisher
    ..The mechanism of uni-directional filament extension beneath the membrane also is discussed. ..