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Ruth Nussinov - One of the best experts on this subject based on the ideXlab platform.
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energetic redistribution in Allostery to execute protein function
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Ruth NussinovAbstract:A perturbation at one site of the protein could cause an effect at a distant site. This important biological phenomenon, termed the “allosteric effect,” is essential for protein regulation and cell signaling, playing an important role in cellular function. Its fundamental functional significance has inspired numerous works aiming to understand how Allostery works. Allostery can involve large, or unobserved, subtle (mainly side-chain) conformational changes (1). Conformational changes are driven by enthalpy. The term “dynamic Allostery” was coined by Cooper and Dryden in the early 1980s to describe Allostery “even in the absence of a macromolecular conformational change” (2). Cooper and Dryden argued that dynamic Allostery is primarily an entropy effect. However, numerous works have been published over the last 20 y taking “dynamic Allostery” to imply a complete absence of conformational change because the authors did not observe such changes (1). Importantly, “dynamic Allostery” without observable conformational changes is still ruled by a population shift between two “distinct” states where a new energetic redistribution favorable for the allosteric (functional) state is either dominated by entropy, enthalpy, or both. Few studies questioned whether enthalpy plays a role in dynamic Allostery as well (1). In PNAS, Kumawat and Chakrabarty (3) demonstrate that indeed even in dynamic Allostery enthalpy plays a role by redistributing internal energies, especially electrostatic interaction energies, among residues upon perturbation (Fig. 1). Fig. 1. The scheme of the electrostatic basis of dynamic Allostery in the PDZ3 domain protein. Dynamic Allostery has no significant conformational change. Upon binding of the peptide (CRIPT), there is no significant enthalpy change, but Kumawat and Chakrabarty (3) reported a redistribution of the electrostatic energies. Such redistribution may propagate to other PDZ domains for the proteins to execute their function. Electrostatics is an established player in function. Decades ago, Warshel (4 … [↵][1]1To whom correspondence may be addressed. Email: jin.liu{at}unthsc.edu or NussinoR{at}mail.nih.gov. [1]: #xref-corresp-1-1
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Allostery an overview of its history concepts methods and applications
PLOS Computational Biology, 2016Co-Authors: Ruth NussinovAbstract:The concept of Allostery has evolved in the past century. In this Editorial, we briefly overview the history of Allostery, from the pre-Allostery nomenclature era starting with the Bohr effect (1904) to the birth of Allostery by Monod and Jacob (1961). We describe the evolution of the Allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic Allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study Allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.
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the role of protein loops and linkers in conformational dynamics and Allostery
Chemical Reviews, 2016Co-Authors: Elena Papaleo, Giorgio Saladino, Matteo Lambrughi, Kresten Lindorfflarsen, Francesco Luigi Gervasio, Ruth NussinovAbstract:Proteins are dynamic entities that undergo a plethora of conformational changes that may take place on a wide range of time scales. These changes can be as small as the rotation of one or a few side-chain dihedral angles or involve concerted motions in larger portions of the three-dimensional structure; both kinds of motions can be important for biological function and Allostery. It is becoming increasingly evident that “connector regions” are important components of the dynamic personality of protein structures. These regions may be either disordered loops, i.e., poorly structured regions connecting secondary structural elements, or linkers that connect entire protein domains. Experimental and computational studies have, however, revealed that these regions are not mere connectors, and their role in Allostery and conformational changes has been emerging in the last few decades. Here we provide a detailed overview of the structural properties and classification of loops and linkers, as well as a discussio...
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Allostery without a conformational change revisiting the paradigm
Current Opinion in Structural Biology, 2015Co-Authors: Ruth Nussinov, Chung Jung TsaiAbstract:Classically, Allostery induces a functional switch through a conformational change. However, lately an increasing number of studies concluded that the Allostery they observe takes place through sheer dynamics. Here we explain that even if a structural comparison between the active and inactive states does not detect a conformational change, it does not mean that there is no conformational change. We list likely reasons for this lack of observation, including crystallization conditions and crystal effects; one of the states is disordered; the structural comparisons disregard the quaternary protein structure; overlooking synergy effects among allosteric effectors and graded incremental switches and too short molecular dynamics simulations. Specific functions are performed by distinct conformations; they emerge through specific interactions between conformationally selected states.
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A Unified View of "How Allostery Works"
PLoS Computational Biology, 2014Co-Authors: Chung Jung Tsai, Ruth NussinovAbstract:The question of how Allostery works was posed almost 50 years ago. Since then it has been the focus of much effort. This is for two reasons: first, the intellectual curiosity of basic science and the desire to understand fundamental phenomena, and second, its vast practical importance. Allostery is at play in all processes in the living cell, and increasingly in drug discovery. Many models have been successfully formulated, and are able to describe Allostery even in the absence of a detailed structural mechanism. However, conceptual schemes designed to qualitatively explain allosteric mechanisms usually lack a quantitative mathematical model, and are unable to link its thermodynamic and structural foundations. This hampers insight into oncogenic mutations in cancer progression and biased agonists' actions. Here, we describe how Allostery works from three different standpoints: thermodynamics, free energy landscape of population shift, and structure; all with exactly the same allosteric descriptors. This results in a unified view which not only clarifies the elusive allosteric mechanism but also provides structural grasp of agonist-mediated signaling pathways, and guides allosteric drug discovery. Of note, the unified view reasons that allosteric coupling (or communication) does not determine the allosteric efficacy; however, a communication channel is what makes potential binding sites allosteric.
Emily J. Parker - One of the best experts on this subject based on the ideXlab platform.
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Using a Combination of Computational and Experimental Techniques to Understand the Molecular Basis for Protein Allostery
Advances in Protein Chemistry, 2020Co-Authors: Wanting Jiao, Emily J. ParkerAbstract:Abstract Allostery is the process by which remote sites of a system are energetically coupled to elicit a functional response. The early models of Allostery such as the Monod–Wyman–Changeux model and the Koshland–Nemethy–Filmer model explain the allosteric behavior of multimeric proteins. However, these models do not explain how Allostery arises from atomic level in detail. Recent developments in computational methods and experimental techniques have led the beginning of a new age in studying Allostery. The combination of computational methods and experiments is a powerful research approach to help answering questions regarding allosteric mechanism at atomic resolution. In this review, three case studies are discussed to illustrate how this combined approach helps to increase our understanding of protein Allostery.
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a single amino acid substitution uncouples catalysis and Allostery in an essential biosynthetic enzyme in mycobacterium tuberculosis
Journal of Biological Chemistry, 2020Co-Authors: Wanting Jiao, Emily J. Parker, Nicola J BlackmoreAbstract:: Allostery exploits the conformational dynamics of enzymes by triggering a shift in population ensembles toward functionally distinct conformational or dynamic states. Allostery extensively regulates the activities of key enzymes within biosynthetic pathways to meet metabolic demand for their end products. Here, we have examined a critical enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS), at the gateway to aromatic amino acid biosynthesis in Mycobacterium tuberculosis, which shows extremely complex dynamic Allostery: three distinct aromatic amino acids jointly communicate occupancy to the active site via subtle changes in dynamics, enabling exquisite fine-tuning of delivery of these essential metabolites. Furthermore, this allosteric mechanism is co-opted by pathway branchpoint enzyme chorismate mutase upon complex formation. In this study, using statistical coupling analysis, site-directed mutagenesis, isothermal calorimetry, small-angle X-ray scattering, and X-ray crystallography analyses, we have pinpointed a critical node within the complex dynamic communication network responsible for this sophisticated allosteric machinery. Through a facile Gly to Pro substitution, we have altered backbone dynamics, completely severing the allosteric signal yet remarkably, generating a nonallosteric enzyme that retains full catalytic activity. We also identified a second residue of prime importance to the inter-enzyme communication with chorismate mutase. Our results reveal that highly complex dynamic Allostery is surprisingly vulnerable and provide further insights into the intimate link between catalysis and Allostery.
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exploring modular Allostery via interchangeable regulatory domains
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Penelope J Cross, Emily J. Parker, Geoffrey B JamesonAbstract:Most proteins comprise two or more domains from a limited suite of protein families. These domains are often rearranged in various combinations through gene fusion events to evolve new protein functions, including the acquisition of protein Allostery through the incorporation of regulatory domains. The enzyme 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS) is the first enzyme of aromatic amino acid biosynthesis and displays a diverse range of allosteric mechanisms. DAH7PSs adopt a common architecture with a shared (β/α)8 catalytic domain which can be attached to an ACT-like or a chorismate mutase regulatory domain that operates via distinct mechanisms. These respective domains confer allosteric regulation by controlling DAH7PS function in response to ligand Tyr or prephenate. Starting with contemporary DAH7PS proteins, two protein chimeras were created, with interchanged regulatory domains. Both engineered proteins were catalytically active and delivered new functional Allostery with switched ligand specificity and allosteric mechanisms delivered by their nonhomologous regulatory domains. This interchangeability of protein domains represents an efficient method not only to engineer Allostery in multidomain proteins but to create a new bifunctional enzyme.
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engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Penelope J Cross, Timothy M Allison, Renwick C J Dobson, Geoffrey B Jameson, Emily J. ParkerAbstract:Allosteric regulation of protein function is a critical component of metabolic control. Its importance is underpinned by the diversity of mechanisms and its presence in all three domains of life. The first enzyme of the aromatic amino acid biosynthesis, 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase, shows remarkable variation in allosteric response and machinery, and both contemporary regulated and unregulated orthologs have been described. To examine the molecular events by which Allostery can evolve, we have generated a chimeric protein by joining the catalytic domain of an unregulated 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with the regulatory domain of a regulated enzyme. We demonstrate that this simple gene fusion event on its own is sufficient to confer functional Allostery to the unregulated enzyme. The fusion protein shares structural similarities with its regulated parent protein and undergoes an analogous major conformational change in response to the binding of allosteric effector tyrosine to the regulatory domain. These findings help delineate a remarkably facile mechanism for the evolution of modular Allostery by domain recruitment.
Vincent J Hilser - One of the best experts on this subject based on the ideXlab platform.
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Allostery in its many disguises from theory to applications
Structure, 2019Co-Authors: Shoshana J Wodak, Vincent J Hilser, Jing Li, Emanuele Paci, Nikolay V Dokholyan, Igor N Berezovsky, Amnon Horovitz, Ivet Bahar, John KaranicolasAbstract:Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Europeen de Calcul Atomique et Moleculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of Allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.
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Simultaneous Tuning of Activation and Repression in Intrinsic Disorder-Mediated Allostery
Biophysical Journal, 2016Co-Authors: Vincent J HilserAbstract:Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling. Like their structured protein counterparts, IDPs can transmit the effects of binding an effector ligand at one site to another functional site, a process known as Allostery. Because Allostery in structured proteins has historically been interpreted in terms of propagated structural changes that are induced by effector binding, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here we show mechanistically how IDPs allosterically transmit signals through a probabilistic process that originates from the simultaneous tuning of both activating and repressing ensembles of the protein, using human glucocorticoid receptor as a model. Moreover, GR modulates this signaling by producing translational isoforms with variable disordered regions. We expect this ensemble model of Allostery will be important in explaining signaling in other IDPs.
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Allostery vs allokairy
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Vincent J Hilser, James A Anderson, Hesam N MotlaghAbstract:A hallmark feature of biological systems is that they are tightly regulated. Whether it is turning genes on and off, controlling cell division, or tuning the activity of enzymes, nature has evolved an intricate array of regulatory measures to ensure that systems can optimally respond to the myriad of environmental queues that determine everything from cell fate to survival. Most often the tuning of an enzyme uses a phenomenon known as Allostery, whereby the binding of substrate to one enzyme molecule is coupled to the binding of another molecule. The end result is that binding at one site can influence subsequent binding events at other sites. Thus, the term “Allostery,” which is derived from the Greek allos meaning “other” and stereos meaning “structure,” describes the ability of biological molecules to transmit the effects of binding spatially through the protein to other sites. The association of oxygen with tetrameric hemoglobin is the prototypical example (1), and indeed almost every enzyme (2) is allosterically controlled by some ligand. However, is the coupling of spatially distinct events the only way to regulate function? In PNAS, Whittington et al. (3) demonstrate how regulation can arise not only by transmitting binding information spatially but also temporally. This mode of regulation forces a reconsideration of the strategies nature has at its disposal to tune biological systems.
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Disordered Allostery: lessons from glucocorticoid receptor
Biophysical Reviews, 2015Co-Authors: Hesam N Motlagh, Jeremy A. Anderson, Jing Li, Vincent J HilserAbstract:Allostery is a biological regulation mechanism of significant importance in cell signaling, metabolism, and disease. Although the ensemble basis of Allostery has been known for years, only recently has emphasis shifted from interpreting allosteric mechanism in terms of discrete structural pathways to ones that focus on the statistical nature of the signal propagation process, providing a vehicle to unify Allostery in structured, dynamic, and disordered systems. In particular, intrinsically disordered (ID) proteins (IDPs), which lack a unique, stable structure, have been directly demonstrated to exhibit Allostery in numerous systems, a reality that challenges traditional structure-based models that focus on allosteric pathways. In this chapter, we will discuss the historical context of Allostery and focus on studies from human glucocorticoid receptor (GR), a member of the steroid hormone receptor (SHR) family. The numerous translational isoforms of the disordered N-terminal domain of GR consist of coupled thermodynamic domains that contribute to the delicate balance of states in the ensemble and hence in vivo activity. The data are quantitatively interpreted using the ensemble allosteric model (EAM) that considers only the intrinsic and measurable energetics of allosteric systems. It is demonstrated that the EAM provides mechanistic insight into the distribution of states in solution and provides an interpretation for how certain translational isoforms of GR display enhanced and repressed transcriptional activities. The ensemble nature of Allostery illuminated from these studies lends credence to the EAM and provides ground rules for Allostery in all systems.
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the ensemble nature of Allostery
Nature, 2014Co-Authors: Hesam N Motlagh, James O Wrabl, Jing Li, Vincent J HilserAbstract:Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that Allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. 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.
Hesam N Motlagh - One of the best experts on this subject based on the ideXlab platform.
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Allostery vs allokairy
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Vincent J Hilser, James A Anderson, Hesam N MotlaghAbstract:A hallmark feature of biological systems is that they are tightly regulated. Whether it is turning genes on and off, controlling cell division, or tuning the activity of enzymes, nature has evolved an intricate array of regulatory measures to ensure that systems can optimally respond to the myriad of environmental queues that determine everything from cell fate to survival. Most often the tuning of an enzyme uses a phenomenon known as Allostery, whereby the binding of substrate to one enzyme molecule is coupled to the binding of another molecule. The end result is that binding at one site can influence subsequent binding events at other sites. Thus, the term “Allostery,” which is derived from the Greek allos meaning “other” and stereos meaning “structure,” describes the ability of biological molecules to transmit the effects of binding spatially through the protein to other sites. The association of oxygen with tetrameric hemoglobin is the prototypical example (1), and indeed almost every enzyme (2) is allosterically controlled by some ligand. However, is the coupling of spatially distinct events the only way to regulate function? In PNAS, Whittington et al. (3) demonstrate how regulation can arise not only by transmitting binding information spatially but also temporally. This mode of regulation forces a reconsideration of the strategies nature has at its disposal to tune biological systems.
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Disordered Allostery: lessons from glucocorticoid receptor
Biophysical Reviews, 2015Co-Authors: Hesam N Motlagh, Jeremy A. Anderson, Jing Li, Vincent J HilserAbstract:Allostery is a biological regulation mechanism of significant importance in cell signaling, metabolism, and disease. Although the ensemble basis of Allostery has been known for years, only recently has emphasis shifted from interpreting allosteric mechanism in terms of discrete structural pathways to ones that focus on the statistical nature of the signal propagation process, providing a vehicle to unify Allostery in structured, dynamic, and disordered systems. In particular, intrinsically disordered (ID) proteins (IDPs), which lack a unique, stable structure, have been directly demonstrated to exhibit Allostery in numerous systems, a reality that challenges traditional structure-based models that focus on allosteric pathways. In this chapter, we will discuss the historical context of Allostery and focus on studies from human glucocorticoid receptor (GR), a member of the steroid hormone receptor (SHR) family. The numerous translational isoforms of the disordered N-terminal domain of GR consist of coupled thermodynamic domains that contribute to the delicate balance of states in the ensemble and hence in vivo activity. The data are quantitatively interpreted using the ensemble allosteric model (EAM) that considers only the intrinsic and measurable energetics of allosteric systems. It is demonstrated that the EAM provides mechanistic insight into the distribution of states in solution and provides an interpretation for how certain translational isoforms of GR display enhanced and repressed transcriptional activities. The ensemble nature of Allostery illuminated from these studies lends credence to the EAM and provides ground rules for Allostery in all systems.
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the ensemble nature of Allostery
Nature, 2014Co-Authors: Hesam N Motlagh, James O Wrabl, Jing Li, Vincent J HilserAbstract:Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that Allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. 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.
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Interplay between Allostery and intrinsic disorder in an ensemble
Biochemical Society Transactions, 2012Co-Authors: Hesam N Motlagh, Jing Li, E. Brad Thompson, Vincent J HilserAbstract:Allostery is a biological phenomenon of critical importance in metabolic regulation and cell signalling. The fundamental premise of classical models that describe Allostery is that structure mediates ‘action at a distance’. Recently, this paradigm has been challenged by the enrichment of IDPs (intrinsically disordered proteins) or ID (intrinsically disordered) segments in transcription factors and signalling pathways of higher organisms, where an allosteric response from external signals is requisite for regulated function. This observation strongly suggests that IDPs elicit the capacity for finely tunable allosteric regulation. Is there a set of transferable ground rules that reconcile these disparate allosteric phenomena? We focus on findings from the human GR (glucocorticoid receptor) which is a nuclear transcription factor in the SHR (steroid hormone receptor) family. GR contains an intrinsically disordered NTD (N-terminal domain) that is obligatory for transcription activity. Different GR translational isoforms have various lengths of NTD and by studying these isoforms we found that the full-length ID NTD consists of two thermodynamically distinct coupled regions. The data are interpreted in the context of an EAM (ensemble allosteric model) that considers only the intrinsic and measurable energetics of allosteric systems. Expansion of the EAM is able to reconcile the paradox that ligands for SHRs can be agonists and antagonists in a cell-context-dependent manner. These findings suggest a mechanism by which SHRs in particular, and IDPs in general, may have evolved to couple thermodynamically distinct ID segments. The ensemble view of Allostery that is illuminated provides organizing principles to unify the description of all allosteric systems and insight into ‘how’ Allostery works.
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structural and energetic basis of Allostery
Annual Review of Biophysics, 2012Co-Authors: Vincent J Hilser, James O Wrabl, Hesam N MotlaghAbstract:Allostery is a biological phenomenon of fundamental importance in regulation and signaling, and efforts to understand this process have led to the development of numerous models. In spite of individual successes in understanding the structural determinants of Allostery in well-documented systems, much less success has been achieved in identifying a set of quantitative and transferable ground rules that provide an understanding of how Allostery works. Are there organizing principles that allow us to relate structurally different proteins, or are the determinants of Allostery unique to each system? Using an ensemble-based model, we show that allosteric phenomena can be formulated in terms of conformational free energies of the cooperative elements in a protein and the coupling interactions between them. Interestingly, the resulting allosteric ground rules provide a framework to reconcile observations that challenge purely structural models of site-to-site coupling, including (a) Allostery in the absence of pathways of structural distortions, (b) Allostery in the absence of any structural change, and (c) the ability of allosteric ligands to act as agonists under some circumstances and antagonists under others. The ensemble view of Allostery that emerges provides insights into the energetic prerequisites of site-to-site coupling and thus into how Allostery works.
Alexandr P Kornev - One of the best experts on this subject based on the ideXlab platform.
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tuning the violin of protein kinases the role of dynamics based Allostery
Iubmb Life, 2019Co-Authors: Lalima G Ahuja, Susan S Taylor, Alexandr P KornevAbstract:: The intricacies of allosteric regulation of protein kinases continue to engage the research community. Allostery, or control from a distance, is seen as a fundamental biomolecular mechanism for proteins. From the traditional methods of conformational selection and induced fit, the field has grown to include the role of protein motions in defining a dynamics-based allosteric approach. Harnessing of these continuous motions in the protein to exert allosteric effects can be defined by a "violin" model that focuses on distributions of protein vibrations as opposed to concerted pathways. According to this model, binding of an allosteric modifier causes global redistribution of dynamics in the protein kinase domain that leads to changes in its catalytic properties. This model is consistent with the "entropy-driven Allostery" mechanism proposed by Cooper and Dryden in 1984 and does not require, but does not exclude, any major structural changes. We provide an overview of practical implementation of the violin model and how it stands amidst the other known models of protein Allostery. Protein kinases have been described as the biomolecules of interest. © 2019 IUBMB Life, 71(6):685-696, 2019.
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Self-organization, entropy and Allostery
Biochemical Society Transactions, 2018Co-Authors: Alexandr P KornevAbstract:Allostery is a fundamental regulatory mechanism in biology. Although generally accepted that it is a dynamics-driven process, the exact molecular mechanism of allosteric signal transmission is hotly debated. We argue that Allostery is as a part of a bigger picture that also includes fractal-like properties of protein interior, hierarchical protein folding and entropy-driven molecular recognition. Although so far all these phenomena were studied separately, they stem from the same common root: self-organization of polypeptide chains and, thus, has to be studied collectively. This merge will allow the cross-referencing of a broad spectrum of multi-disciplinary data facilitating progress in all these fields.
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Allostery through the computational microscope camp activation of a canonical signalling domain
Nature Communications, 2015Co-Authors: Robert D Malmstrom, Alexandr P Kornev, Susan S Taylor, Rommie E AmaroAbstract:Allostery, communication between distant parts of a protein, is a key element of enzyme catalysis. Here the authors combine existing experimental data with molecular dynamics simulations and Markov state models to provide insight into the mechanism of ligand-induced Allostery within the cyclicnucleotide-binding domain of protein kinase A.
