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Journal articles on the topic 'Allosteric binding'

Author: Grafiati

Published: 3 June 2025

Last updated: 31 July 2025

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1

Guan, Xingyue, Cheng Tan, Wenfei Li, Wei Wang, and D. Thirumalai. "Role of water-bridged interactions in metal ion coupled protein allostery." PLOS Computational Biology 18, no. 6 (2022): e1010195. http://dx.doi.org/10.1371/journal.pcbi.1010195.

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Allosteric communication between distant parts of proteins controls many cellular functions, in which metal ions are widely utilized as effectors to trigger the allosteric cascade. Due to the involvement of strong coordination interactions, the energy landscape dictating the metal ion binding is intrinsically rugged. How metal ions achieve fast binding by overcoming the landscape ruggedness and thereby efficiently mediate protein allostery is elusive. By performing molecular dynamics simulations for the Ca2+ binding mediated allostery of the calmodulin (CaM) domains, each containing two Ca2+ b

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2

Kuznetsov, Aleksei, and Jaak Järv. "Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit." Open Life Sciences 4, no. 2 (2009): 131–41. http://dx.doi.org/10.2478/s11535-009-0012-6.

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AbstractProtein kinase A (cAMP dependent protein kinase catalytic subunit, EC 2.7.11.11) binds simultaneously ATP and a phosphorylatable peptide. These structurally dissimilar allosteric ligands influence the binding effectiveness of each other. The same situation is observed with substrate congeners, which reversibly inhibit the enzyme. In this review these allosteric effects are quantified using the interaction factor, which compares binding effectiveness of ligands with the free enzyme and the pre-loaded enzyme complex containing another ligand. This analysis revealed that the allosteric ef

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Xu, Yunyao, Dongyu Zhang, Rivkah Rogawski, Crina M. Nimigean, and Ann E. McDermott. "Identifying coupled clusters of allostery participants through chemical shift perturbations." Proceedings of the National Academy of Sciences 116, no. 6 (2019): 2078–85. http://dx.doi.org/10.1073/pnas.1811168116.

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Allosteric couplings underlie many cellular signaling processes and provide an exciting avenue for development of new diagnostics and therapeutics. A general method for identifying important residues in allosteric mechanisms would be very useful, but remains elusive due to the complexity of long-range phenomena. Here, we introduce an NMR method to identify residues involved in allosteric coupling between two ligand-binding sites in a protein, which we call chemical shift detection of allostery participants (CAP). Networks of functional groups responding to each ligand are defined through corre

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Ugbaja, Samuel C., Isiaka A. Lawal, Bahijjahtu H. Abubakar, Aganze G. Mushebenge, Monsurat M. Lawal, and Hezekiel M. Kumalo. "Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer’s Disease Therapy." Molecules 27, no. 14 (2022): 4372. http://dx.doi.org/10.3390/molecules27144372.

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In over a century since its discovery, Alzheimer’s disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at

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Balboni, Beatrice, Mirco Masi, Walter Rocchia, Stefania Girotto та Andrea Cavalli. "GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?" International Journal of Molecular Sciences 24, № 8 (2023): 7541. http://dx.doi.org/10.3390/ijms24087541.

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Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similari

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Abrusán, György, and Joseph A. Marsh. "Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes." Molecular Biology and Evolution 36, no. 8 (2019): 1711–27. http://dx.doi.org/10.1093/molbev/msz093.

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Abstract The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the e

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Zhou, Tao, Huiling Zhang, Xiaoting Yu, et al. "Fc-Binding Cyclopeptide Induces Allostery from Fc to Fab: Revealed Through in Silico Structural Analysis to Anti-Phenobarbital Antibody." Foods 14, no. 8 (2025): 1360. https://doi.org/10.3390/foods14081360.

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Allostery is a fundamental biological phenomenon that occurs when a molecule binds to a protein’s allosteric site, triggering conformational changes that regulate the protein’s activity. However, allostery in antibodies remains largely unexplored, and only a few reports have focused on allostery from antigen-binding fragments (Fab) to crystallizable fragments (Fc). But this study, using anti-phenobarbital antibodies—which are widely applied for detecting the potential health food adulterant phenobarbital—as a model and employing multiple computational methods, is the first to identify a cyclop

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Patrick, John W., Christopher D. Boone, Wen Liu, et al. "Allostery revealed within lipid binding events to membrane proteins." Proceedings of the National Academy of Sciences 115, no. 12 (2018): 2976–81. http://dx.doi.org/10.1073/pnas.1719813115.

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Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein−lipid assemblies. Despite this inherent complexity, the identification of specific protein−lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as alloste

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9

Capdevila, Daiana A., Joseph J. Braymer, Katherine A. Edmonds, Hongwei Wu, and David P. Giedroc. "Entropy redistribution controls allostery in a metalloregulatory protein." Proceedings of the National Academy of Sciences 114, no. 17 (2017): 4424–29. http://dx.doi.org/10.1073/pnas.1620665114.

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Allosteric communication between two ligand-binding sites in a protein is a central aspect of biological regulation that remains mechanistically unclear. Here we show that perturbations in equilibrium picosecond–nanosecond motions impact zinc (Zn)-induced allosteric inhibition of DNA binding by the Zn efflux repressor CzrA (chromosomal zinc-regulated repressor). DNA binding leads to an unanticipated increase in methyl side-chain flexibility and thus stabilizes the complex entropically; Zn binding redistributes these motions, inhibiting formation of the DNA complex by restricting coupled fast m

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Thirumalai, D., and Changbong Hyeon. "Signalling networks and dynamics of allosteric transitions in bacterial chaperonin GroEL: implications for iterative annealing of misfolded proteins." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170182. http://dx.doi.org/10.1098/rstb.2017.0182.

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Signal transmission at the molecular level in many biological complexes occurs through allosteric transitions. Allostery describes the responses of a complex to binding of ligands at sites that are spatially well separated from the binding region. We describe the structural perturbation method, based on phonon propagation in solids, which can be used to determine the signal-transmitting allostery wiring diagram (AWD) in large but finite-sized biological complexes. Application to the bacterial chaperonin GroEL–GroES complex shows that the AWD determined from structures also drives the allosteri

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Abrusán, György, David B. Ascher, and Michael Inouye. "Known allosteric proteins have central roles in genetic disease." PLOS Computational Biology 18, no. 2 (2022): e1009806. http://dx.doi.org/10.1371/journal.pcbi.1009806.

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Allostery is a form of protein regulation, where ligands that bind sites located apart from the active site can modify the activity of the protein. The molecular mechanisms of allostery have been extensively studied, because allosteric sites are less conserved than active sites, and drugs targeting them are more specific than drugs binding the active sites. Here we quantify the importance of allostery in genetic disease. We show that 1) known allosteric proteins are central in disease networks, contribute to genetic disease and comorbidities much more than non-allosteric proteins, and there is

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Byun, J. A., M. Akimoto, B. VanSchouwen, T. S. Lazarou, S. S. Taylor, and G. Melacini. "Allosteric pluripotency as revealed by protein kinase A." Science Advances 6, no. 25 (2020): eabb1250. http://dx.doi.org/10.1126/sciadv.abb1250.

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The functional response of a signaling system to an allosteric stimulus often depends on subcellular conditions, a phenomenon known as pluripotent allostery. For example, a single allosteric modulator, Rp-cAMPS, of the prototypical protein kinase A (PKA) switches from antagonist to agonist depending on MgATP levels. However, the mechanism underlying such pluripotent allostery has remained elusive for decades. Using nuclear magnetic resonance spectroscopy, ensemble models, kinase assays, and molecular dynamics simulations, we show that allosteric pluripotency arises from surprisingly divergent

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13

Christopoulos, A., L. T. May, V. A. Avlani, and P. M. Sexton. "G-protein-coupled receptor allosterism: the promise and the problem(s)." Biochemical Society Transactions 32, no. 5 (2004): 873–77. http://dx.doi.org/10.1042/bst0320873.

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Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validatio

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Mitchell, Michael R., Tsvi Tlusty, and Stanislas Leibler. "Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings." Proceedings of the National Academy of Sciences 113, no. 40 (2016): E5847—E5855. http://dx.doi.org/10.1073/pnas.1609462113.

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In many proteins, especially allosteric proteins that communicate regulatory states from allosteric to active sites, structural deformations are functionally important. To understand these deformations, dynamical experiments are ideal but challenging. Using static structural information, although more limited than dynamical analysis, is much more accessible. Underused for protein analysis, strain is the natural quantity for studying local deformations. We calculate strain tensor fields for proteins deformed by ligands or thermal fluctuations using crystal and NMR structure ensembles. Strains—p

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15

Gupta, Grace, and Gennady Verkhivker. "Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking." International Journal of Molecular Sciences 25, no. 9 (2024): 4955. http://dx.doi.org/10.3390/ijms25094955.

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Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite the increasing interest and effort in discovering allosteric inhibitors of the viral activity and interactions with the host receptor ACE2. The challenges of discovering allosteric modulators of the SARS-CoV-2 spike proteins are associated with the diversity of cryptic allosteric sites and complex molecular mechanisms that can be employed by allosteric ligands, including the alteration of the conformational equilibrium of spike protein and preferential stabilization of specific functiona

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Alshahrani, Mohammed, Grace Gupta, Sian Xiao, Peng Tao, and Gennady Verkhivker. "Comparative Analysis of Conformational Dynamics and Systematic Characterization of Cryptic Pockets in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 Spike Complexes with the ACE2 Host Receptor: Confluence of Binding and Structural Plasticity in Mediating Networks of Conserved Allosteric Sites." Viruses 15, no. 10 (2023): 2073. http://dx.doi.org/10.3390/v15102073.

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In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabiliza

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Lisi, George P., Kyle W. East, Victor S. Batista, and J. Patrick Loria. "Altering the allosteric pathway in IGPS suppresses millisecond motions and catalytic activity." Proceedings of the National Academy of Sciences 114, no. 17 (2017): E3414—E3423. http://dx.doi.org/10.1073/pnas.1700448114.

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Imidazole glycerol phosphate synthase (IGPS) is a V-type allosteric enzyme, meaning that its catalytic rate is critically dependent on activation by its allosteric ligand, N′-[(5′-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (PRFAR). The allosteric mechanism of IGPS is reliant on millisecond conformational motions for efficient catalysis. We engineered four mutants of IGPS designed to disrupt millisecond motions and allosteric coupling to identify regions that are critical to IGPS function. Multiple-quantum Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion exp

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Gruber, Ranit, and Amnon Horovitz. "Unpicking allosteric mechanisms of homo-oligomeric proteins by determining their successive ligand binding constants." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170176. http://dx.doi.org/10.1098/rstb.2017.0176.

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Advances in native mass spectrometry and single-molecule techniques have made it possible in recent years to determine the values of successive ligand binding constants for large multi-subunit proteins. Given these values, it is possible to distinguish between different allosteric mechanisms and, thus, obtain insights into how various bio-molecular machines work. Here, we describe for ring-shaped homo-oligomers, in particular, how the relationship between the values of successive ligand binding constants is diagnostic for concerted, sequential and probabilistic allosteric mechanisms. This arti

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Tan, Zhen Wah, Enrico Guarnera, Wei-Ven Tee, and Igor N. Berezovsky. "AlloSigMA 2: paving the way to designing allosteric effectors and to exploring allosteric effects of mutations." Nucleic Acids Research 48, W1 (2020): W116—W124. http://dx.doi.org/10.1093/nar/gkaa338.

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Abstract The AlloSigMA 2 server provides an interactive platform for exploring the allosteric signaling caused by ligand binding and/or mutations, for analyzing the allosteric effects of mutations and for detecting potential cancer drivers and pathogenic nsSNPs. It can also be used for searching latent allosteric sites and for computationally designing allosteric effectors for these sites with required agonist/antagonist activity. The server is based on the implementation of the Structure-Based Statistical Mechanical Model of Allostery (SBSMMA), which allows one to evaluate the allosteric free

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Nerín-Fonz, Francho, and Zoe Cournia. "Machine learning approaches in predicting allosteric sites." Current Opinion in Structural Biology 85 (February 13, 2024): 102774. https://doi.org/10.5281/zenodo.10658858.

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Allosteric regulation is a fundamental biological mechanism that can control critical cellular processes via allosteric modulator binding to protein distal functional sites. The advantages of allosteric modulators over orthosteric ones have sparked the development of numerous computational approaches, such as the identification of allosteric binding sites, to facilitate allosteric drug discovery. Building on the success of machine learning (ML) models for solving complex problems in biology and chemistry, several ML models for predicting allosteric sites have been developed. In this review, we

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Suplatov, D. А., and V. К. Švedas. "Study of Functional and Allosteric Sites in Protein Superfamilies." Acta Naturae 7, no. 4 (2015): 34–45. http://dx.doi.org/10.32607/20758251-2015-7-4-34-45.

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The interaction of proteins (enzymes) with a variety of low-molecular-weight compounds, as well as protein-protein interactions, is the most important factor in the regulation of their functional properties. To date, research effort has routinely focused on studying ligand binding to the functional sites of proteins (active sites of enzymes), whereas the molecular mechanisms of allosteric regulation, as well as binding to other pockets and cavities in protein structures, remained poorly understood. Recent studies have shown that allostery may be an intrinsic property of virtually all proteins.

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Wang, Xuebin, Ning Liu, Nuan Li, Shaoyong Lu, and Zongtao Chai. "Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7)." Biomolecules 15, no. 6 (2025): 749. https://doi.org/10.3390/biom15060749.

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Ubiquitin-specific protease 7 (USP7), a deubiquitinase enzyme responsible for removing ubiquitin (Ub) from target proteins, plays a crucial role in oncogenic pathways and has been implicated in various human diseases. X-ray crystallography has revealed distinct conformations of USP7, including apo (ligand-free), allosteric inhibitor-, and Ub-bound states. However, the dynamic mechanisms underlying the allosteric inhibition of USP7 remain unclear. This study investigates the effect of allosteric inhibitor binding on the dynamics of USP7 through multiple replica molecular dynamics simulations. O

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Sengupta, Ushnish, and Birgit Strodel. "Markov models for the elucidation of allosteric regulation." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170178. http://dx.doi.org/10.1098/rstb.2017.0178.

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Allosteric regulation refers to the process where the effect of binding of a ligand at one site of a protein is transmitted to another, often distant, functional site. In recent years, it has been demonstrated that allosteric mechanisms can be understood by the conformational ensembles of a protein. Molecular dynamics (MD) simulations are often used for the study of protein allostery as they provide an atomistic view of the dynamics of a protein. However, given the wealth of detailed information hidden in MD data, one has to apply a method that allows extraction of the conformational ensembles

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Kumawat, Amit, and Suman Chakrabarty. "Hidden electrostatic basis of dynamic allostery in a PDZ domain." Proceedings of the National Academy of Sciences 114, no. 29 (2017): E5825—E5834. http://dx.doi.org/10.1073/pnas.1705311114.

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Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to

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Bozovic, Olga, Claudio Zanobini, Adnan Gulzar, et al. "Real-time observation of ligand-induced allosteric transitions in a PDZ domain." Proceedings of the National Academy of Sciences 117, no. 42 (2020): 26031–39. http://dx.doi.org/10.1073/pnas.2012999117.

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While allostery is of paramount importance for protein regulation, the underlying dynamical process of ligand (un)binding at one site, resulting time evolution of the protein structure, and change of the binding affinity at a remote site are not well understood. Here the ligand-induced conformational transition in a widely studied model system of allostery, the PDZ2 domain, is investigated by transient infrared spectroscopy accompanied by molecular dynamics simulations. To this end, an azobenzene-derived photoswitch is linked to a peptide ligand in a way that its binding affinity to the PDZ2 d

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Chen, Xiaolan, Chunqiong Li, Dada Wang, Yu Chen, and Na Zhang. "Recent Advances in the Discovery of CK2 Allosteric Inhibitors: From Traditional Screening to Structure-Based Design." Molecules 25, no. 4 (2020): 870. http://dx.doi.org/10.3390/molecules25040870.

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Protein kinase (CK2) has emerged as an attractive cancer therapeutic target and recent efforts have been made to develop its inhibitors. However, the development of selective inhibitors remains challenging because of the highly conserved ATP-binding pocket (orthosteric site) of kinase family. As an alternative strategy, allosteric inhibitors, by targeting the much more diversified allosteric site relative to the conserved ATP-binding site, achieve better pharmacological advantages than orthosteric inhibitors. Traditional serendipitous screening and structure-based design are robust tools for t

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May, Meiling R., John T. Bettridge, and Stephen Desiderio. "Binding and allosteric transmission of histone H3 Lys-4 trimethylation to the recombinase RAG-1 are separable functions of the RAG-2 plant homeodomain finger." Journal of Biological Chemistry 295, no. 27 (2020): 9052–60. http://dx.doi.org/10.1074/jbc.ra120.014382.

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V(D)J recombination is initiated by the recombination-activating gene protein (RAG) recombinase, consisting of RAG-1 and RAG-2 subunits. The susceptibility of gene segments to cleavage by RAG is associated with gene transcription and with epigenetic marks characteristic of active chromatin, including histone H3 trimethylated at lysine 4 (H3K4me3). Binding of H3K4me3 by a plant homeodomain (PHD) in RAG-2 induces conformational changes in RAG-1, allosterically stimulating substrate binding and catalysis. To better understand the path of allostery from the RAG-2 PHD finger to RAG-1, here we emplo

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Jakowiecki, Jakub, Renata Abel, Urszula Orzeł, Paweł Pasznik, Robert Preissner, and Sławomir Filipek. "Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol—A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling." Molecules 26, no. 9 (2021): 2456. http://dx.doi.org/10.3390/molecules26092456.

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The CB1 cannabinoid receptor (CB1R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB1R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB1R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ9-THC, was docked to the orthosteri

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Yuan, Jiayi, Chen Jiang, Junmei Wang, et al. "In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators." Molecules 27, no. 2 (2022): 453. http://dx.doi.org/10.3390/molecules27020453.

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Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-

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Lisnyak, Yu. V., and A. V. Martynov. "Ligand-binding sites on the Mycobacterium tuberculosis urease." Annals of Mechnikov Institute, no. 3 (October 1, 2017): 37–46. https://doi.org/10.5281/zenodo.1000136.

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<strong>Introduction</strong><strong>.</strong> <em>Mycobacterium tuberculosis</em> is the causative agent of tuberculosis that remains a serious medical and social health problem. Despite intensive efforts have been made in the past decade, there are no new efficient anti-tuberculosis drugs today, and that need is growing due to the spread of drug-resistant strains of <em>M.tuberculosis</em>. <em>M. tuberculosis</em> urease (MTU), being an important factor of the bacterium viability and virulence, is an attractive target for anti-tuberculosis drugs acting by inhibition of urease activity. How

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Gao, Zhan-Guo, Kiran S. Toti, Ryan Campbell, R. Rama Suresh, Huijun Yang, and Kenneth A. Jacobson. "Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands." Cells 9, no. 5 (2020): 1200. http://dx.doi.org/10.3390/cells9051200.

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Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive o

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Stock, Gerhard, and Peter Hamm. "A non-equilibrium approach to allosteric communication." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170187. http://dx.doi.org/10.1098/rstb.2017.0187.

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While the theory of protein folding is well developed, including concepts such as rugged energy landscape, folding funnel, etc., the same degree of understanding has not been reached for the description of the dynamics of allosteric transitions in proteins. This is not only due to the small size of the structural change upon ligand binding to an allosteric site, but also due to challenges in designing experiments that directly observe such an allosteric transition. On the basis of recent pump-probe-type experiments (Buchli et al. 2013 Proc. Natl Acad. Sci. USA 110 , 11 725–11 730. ( doi:10.107

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Jiao, Wanting. "Computational investigations of allostery in aromatic amino acid biosynthetic enzymes." Biochemical Society Transactions 49, no. 1 (2021): 415–29. http://dx.doi.org/10.1042/bst20200741.

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Allostery, in which binding of ligands to remote sites causes a functional change in the active sites, is a fascinating phenomenon observed in enzymes. Allostery can occur either with or without significant conformational changes in the enzymes, and the molecular basis of its mechanism can be difficult to decipher using only experimental techniques. Computational tools for analyzing enzyme sequences, structures, and dynamics can provide insights into the allosteric mechanism at the atomic level. Combining computational and experimental methods offers a powerful strategy for the study of enzyme

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Meng, Wenli, Eugenia M. Clerico, Natalie McArthur, and Lila M. Gierasch. "Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces." Proceedings of the National Academy of Sciences 115, no. 47 (2018): 11970–75. http://dx.doi.org/10.1073/pnas.1811105115.

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The 70-kDa heat shock proteins (Hsp70s) are molecular chaperones that perform a wide range of critical cellular functions. They assist in the folding of newly synthesized proteins, facilitate assembly of specific protein complexes, shepherd proteins across membranes, and prevent protein misfolding and aggregation. Hsp70s perform these functions by a conserved mechanism that relies on allosteric cycles of nucleotide-modulated binding and release of client proteins. Current models for Hsp70 allostery have come from extensive study of the bacterial Hsp70, DnaK. Extending our understanding to euka

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Korczynska, Magdalena, Mary J. Clark, Celine Valant, et al. "Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor." Proceedings of the National Academy of Sciences 115, no. 10 (2018): E2419—E2428. http://dx.doi.org/10.1073/pnas.1718037115.

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Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M2 mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antago

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Perez-Riba, Albert, Marie Synakewicz, and Laura S. Itzhaki. "Folding cooperativity and allosteric function in the tandem-repeat protein class." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170188. http://dx.doi.org/10.1098/rstb.2017.0188.

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The term allostery was originally developed to describe structural changes in one binding site induced by the interaction of a partner molecule with a distant binding site, and it has been studied in depth in the field of enzymology. Here, we discuss the concept of action at a distance in relation to the folding and function of the solenoid class of tandem-repeat proteins such as tetratricopeptide repeats (TPRs) and ankyrin repeats. Distantly located repeats fold cooperatively, even though only nearest-neighbour interactions exist in these proteins. A number of repeat-protein scaffolds have be

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Zhou, Qingtong, Wanjing Guo, Antao Dai, et al. "Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening." Biomolecules 11, no. 7 (2021): 929. http://dx.doi.org/10.3390/biom11070929.

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Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interaction

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Peter, Sonja, Lydia Siragusa, Morgan Thomas, et al. "Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential." Journal of Chemical Information and Modeling 64, no. 21 (2024): 8176–92. https://doi.org/10.1021/acs.jcim.4c00819.

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The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations of allosteric modulation, and yet few drugs target them. This gap highlights the need for a deeper understanding of allosteric modulation in GPCR drug discovery. The current work introduces a systematic annotation scheme to structurally classify GPCR binding sites based on receptor class, transmembrane helix contacts, and, for membrane-facing sites, membrane sublocation. This GPCR specific annotation scheme was applied to 107 GPCR structures bound by small molecules contribut

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Urbanský, Marek, Jan Proška, Jan Říčný, and Pavel Drašar. "Truxillic Acid Derivatives, Neuromuscular Blocking Agents with Very High Affinity for the Allosteric Binding Site of Muscarinic Acetylcholine Receptors." Collection of Czechoslovak Chemical Communications 64, no. 12 (1999): 1980–92. http://dx.doi.org/10.1135/cccc19991980.

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Bis-quaternary salts of 3-piperidinopropyl esters of α-truxillic acid were synthesized in order to study their allosteric action on muscarinic acetylcholine receptor. Using radioligand binding studies, it has been demonstrated that most of prepared compounds bind with high affinity to the allosteric binding site of M2 muscarinic receptor subtype (Kd values in the range 1-10 nM). Bulky substitution of the quaternary ammonium center led to effective positive modulators of [3H]N-methylscopolamine binding to M2 receptors. Due to its high allosteric potency, the structure of phenacyl derivative see

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40

Zlobin, A. S., D. А. Suplatov, K. Е. Kopylov, and V. К. Švedas. "CASBench: A Benchmarking Set of Proteins with Annotated Catalytic and Allosteric Sites in Their Structures." Acta Naturae 11, no. 1 (2019): 74–80. http://dx.doi.org/10.32607/20758251-2019-11-1-74-80.

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In recent years, the phenomenon of allostery has witnessed growing attention driven by a fundamental interest in new ways to regulate the functional properties of proteins, as well as the prospects of using allosteric sites as targets to design novel drugs with lower toxicity due to a higher selectivity of binding and specificity of the mechanism of action. The currently available bioinformatic methods can sometimes correctly detect previously unknown ligand binding sites in protein structures. However, the development of universal and more efficient approaches requires a deeper understanding

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Verkhivker, Gennady, Steve Agajanian, Ryan Kassab, and Keerthi Krishnan. "Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms." Biomolecules 12, no. 7 (2022): 964. http://dx.doi.org/10.3390/biom12070964.

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In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-CoV-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control point

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Cook, Ian, Ting Wang, and Thomas S. Leyh. "Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation." Proceedings of the National Academy of Sciences 114, no. 27 (2017): E5317—E5324. http://dx.doi.org/10.1073/pnas.1704500114.

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Monoamine neurotransmitters are among the hundreds of signaling small molecules whose target interactions are switched “on” and “off” via transfer of the sulfuryl-moiety (–SO3) from PAPS (3′-phosphoadenosine 5′-phosphosulfate) to the hydroxyls and amines of their scaffolds. These transfer reactions are catalyzed by a small family of broad-specificity enzymes—the human cytosolic sulfotransferases (SULTs). The first structure of a SULT allosteric-binding site (that of SULT1A1) has recently come to light. The site is conserved among SULT1 family members and is promiscuous—it binds catechins, a na

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Sumbul, Fidan, Saliha Ece Acuner-Ozbabacan, and Turkan Haliloglu. "Allosteric Dynamic Control of Binding." Biophysical Journal 109, no. 6 (2015): 1190–201. http://dx.doi.org/10.1016/j.bpj.2015.08.011.

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Hadzipasic, Adelajda, Christopher Wilson, Vy Nguyen, et al. "Ancient origins of allosteric activation in a Ser-Thr kinase." Science 367, no. 6480 (2020): 912–17. http://dx.doi.org/10.1126/science.aay9959.

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A myriad of cellular events are regulated by allostery; therefore, evolution of this process is of fundamental interest. Here, we use ancestral sequence reconstruction to resurrect ancestors of two colocalizing proteins, Aurora A kinase and its allosteric activator TPX2 (targeting protein for Xklp2), to experimentally characterize the evolutionary path of allosteric activation. Autophosphorylation of the activation loop is the most ancient activation mechanism; it is fully developed in the oldest kinase ancestor and has remained stable over 1 billion years of evolution. As the microtubule-asso

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Xu, Yunyao, Manasi P. Bhate, and Ann E. McDermott. "Transmembrane allosteric energetics characterization for strong coupling between proton and potassium ion binding in the KcsA channel." Proceedings of the National Academy of Sciences 114, no. 33 (2017): 8788–93. http://dx.doi.org/10.1073/pnas.1701330114.

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The slow spontaneous inactivation of potassium channels exhibits classic signatures of transmembrane allostery. A variety of data support a model in which the loss of K+ ions from the selectivity filter is a major factor in promoting inactivation, which defeats transmission, and is allosterically coupled to protonation of key channel activation residues, more than 30 Å from the K+ ion binding site. We show that proton binding at the intracellular pH sensor perturbs the potassium affinity at the extracellular selectivity filter by more than three orders of magnitude for the full-length wild-typ

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Li, Mengrong, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, and Jingjing Guo. "Understanding the Allosteric Modulation of PTH1R by a Negative Allosteric Modulator." Cells 12, no. 1 (2022): 41. http://dx.doi.org/10.3390/cells12010041.

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The parathyroid hormone type 1 receptor (PTH1R) acts as a canonical class B G protein-coupled receptor, regulating crucial functions including calcium homeostasis and bone formation. The identification and development of PTH1R non-peptide allosteric modulators have obtained widespread attention. It has been found that a negative allosteric modulator (NAM) could inhibit the activation of PTH1R, but the implied mechanism remains unclear. Herein, extensive molecular dynamics simulations together with multiple analytical approaches are utilized to unravel the mechanism of PTH1R allosteric inhibiti

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Almahmoud, Suliman, та Haizhen A. Zhong. "Molecular Modeling of Allosteric Site of Isoform-Specific Inhibition of the Peroxisome Proliferator-Activated Receptor PPARγ". Biomolecules 12, № 11 (2022): 1614. http://dx.doi.org/10.3390/biom12111614.

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The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and controls a number of gene expressions. The ligand binding domain (LBD) of PPARγ is large and involves two binding sites: orthosteric and allosteric binding sites. Increased evidence has shown that PPARγ is an oncogene and thus the PPARγ antagonists have potential as anticancer agents. In this paper, we use Glide Dock approach to determine which binding site, orthosteric or allosteric, would be a preferred pocket for PPARγ antagonist binding, though antidiabetic drugs such as thiazolidinediones (TZDs) bind to

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Zhuravleva, Anastasia, and Lila M. Gierasch. "Substrate-binding domain conformational dynamics mediate Hsp70 allostery." Proceedings of the National Academy of Sciences 112, no. 22 (2015): E2865—E2873. http://dx.doi.org/10.1073/pnas.1506692112.

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Binding of ATP to the N-terminal nucleotide-binding domain (NBD) of heat shock protein 70 (Hsp70) molecular chaperones reduces the affinity of their C-terminal substrate-binding domain (SBD) for unfolded protein substrates. ATP binding to the NBD leads to docking between NBD and βSBD and releasing of the α-helical lid that covers the substrate-binding cleft in the SBD. However, these structural changes alone do not fully account for the allosteric mechanism of modulation of substrate affinity and binding kinetics. Through a multipronged study of the Escherichia coli Hsp70 DnaK, we found that c

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Mayer, Matthias P. "Intra-molecular pathways of allosteric control in Hsp70s." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (2018): 20170183. http://dx.doi.org/10.1098/rstb.2017.0183.

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The 70 kDa heat-shock protein (Hsp70) is undoubtedly the most versatile of all molecular chaperones. Hsp70 is involved in numerous cellular protein folding processes, accompanying proteins throughout their lifespan from de novo folding at the ribosome to degradation at the proteasome, surveilling protein stability and functionality. Several properties of this ATP-dependent chaperone constitute the molecular basis for this versatility. With its substrate binding domain (SBD), Hsp70 transiently interacts with a short degenerative linear sequence motif found practically in all proteins and, in ad

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Brunori, Maurizio, and Adriana Erica Miele. "Modulation of Allosteric Control and Evolution of Hemoglobin." Biomolecules 13, no. 3 (2023): 572. http://dx.doi.org/10.3390/biom13030572.

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Allostery arises when a ligand-induced change in shape of a binding site of a protein is coupled to a tertiary/quaternary conformational change with a consequent modulation of functional properties. The two-state allosteric model of Monod, Wyman and Changeux [J. Mol. Biol. 1965; 12, 88–118] is an elegant and effective theory to account for protein regulation and control. Tetrameric hemoglobin (Hb), the oxygen transporter of all vertebrates, has been for decades the ideal system to test for the validity of the MWC theory. The small ligands affecting Hb’s behavior (organic phosphates, protons, b

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