Is allostery an intrinsic property of all dynamic proteins?
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Abstract Allostery involves coupling of conformational changes between two widely separated binding sites. The common view holds that allosteric proteins are symmetric oligomers, with each subunit existing in “at least” two conformational states with a different affinity for ligands. Recent observations such as the allosteric behavior of myoglobin, a classical example of a nonallosteric protein, call into question the existing allosteric dogma. Here we argue that all (nonfibrous) proteins are potentially allosteric. Allostery is a consequence of re‐distributions of protein conformational ensembles. In a nonallosteric protein, the binding site shape may not show a concerted second‐site change and enzyme kinetics may not reflect an allosteric transition. Nevertheless, appropriate ligands, point mutations, or external conditions may facilitate a population shift, leading a presumably nonallosteric protein to behave allosterically. In principle, practically any potential drug binding to the protein surface can alter the conformational redistribution. The question is its effectiveness in the redistribution of the ensemble, affecting the protein binding sites and its function. Here, we review experimental observations validating this view of protein allostery. Proteins 2004. © 2004 Wiley‐Liss, Inc.Keywords:
Allosteric enzyme
Redistribution
Protein Dynamics
Allostery is one of the cornerstones of biological function, as it plays a fundamental role in regulating protein activity. The modelling of allostery has gradually moved from a conformation-based framework, linked to structural changes, to dynamics-based allostery, whereby the effects of ligand binding propagate via signal transduction from the allosteric site to other regions of the protein via inter-residue interactions. Characterising such allosteric signalling pathways, which do not necessarily lead to conformational changes, has been pursued experimentally and complemented by computational analysis of protein networks to detect subtle dynamic propagation paths. Considering allostery from the perspective of signal transduction broadens the understanding of allosteric mechanisms, underscores the importance of protein topology, and can provide insights into allosteric drug design.
Allosteric enzyme
Protein Dynamics
Signaling proteins
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Glucokinase
Protein Dynamics
Allosteric enzyme
Hydrogen–deuterium exchange
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Beef liver glutamate dehydrogenase is one of a number of allosteric, or regulatory, enzymes which are known to demonstrate reversible selfaggregation in vitro. In this report we present evidence that aggregation plays an important role in the allosteric control of this enzyme. Quasielastic light scattering spectroscopy is used in conjunction with biochemical determinations of enzyme activity in order to quantitatively characterize the relation between aggregation and enzyme activity. A mathematical model is presented which successfully predicts this experimentally observed relation and elucidates the specific role of aggregation in the allosteric regulation of this enzyme. We find that the net effect of the aggregation is: (1) to cause the allosteric transition of the enzyme from inactive to active form to occur at a lower level of allosteric activation, where the level of allosteric activation is a measure of the relative concentrations of allosteric activators and inhibitors; and (2) to make this allosteric transition a more abrupt function of the level of allosteric activation . This finding has important implications for the functioning of this enzyme as a control element in protein metabolism.
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Abstract Allostery involves coupling of conformational changes between two widely separated binding sites. The common view holds that allosteric proteins are symmetric oligomers, with each subunit existing in “at least” two conformational states with a different affinity for ligands. Recent observations such as the allosteric behavior of myoglobin, a classical example of a nonallosteric protein, call into question the existing allosteric dogma. Here we argue that all (nonfibrous) proteins are potentially allosteric. Allostery is a consequence of re‐distributions of protein conformational ensembles. In a nonallosteric protein, the binding site shape may not show a concerted second‐site change and enzyme kinetics may not reflect an allosteric transition. Nevertheless, appropriate ligands, point mutations, or external conditions may facilitate a population shift, leading a presumably nonallosteric protein to behave allosterically. In principle, practically any potential drug binding to the protein surface can alter the conformational redistribution. The question is its effectiveness in the redistribution of the ensemble, affecting the protein binding sites and its function. Here, we review experimental observations validating this view of protein allostery. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Allosteric enzyme
Redistribution
Protein Dynamics
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Allosteric enzyme
Conformational change
Protein Dynamics
Conformational ensembles
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Allosteric enzyme
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Allosteric regulation of protein function, the process by which binding of an effector molecule provokes a functional response from a distal site, is critical for metabolic pathways. Yet, the way the allosteric signal is communicated remains elusive, especially in dynamic, entropically driven regulation mechanisms for which no major conformational changes are observed. To identify these dynamic allosteric communication networks, we have developed an approach that monitors the pKa variations of ionizable residues over the course of molecular dynamics simulations performed in the presence and absence of an allosteric regulator. As the pKa of ionizable residues depends on their environment, it represents a simple metric to monitor changes in several complex factors induced by binding an allosteric effector. These factors include Coulombic interactions, hydrogen bonding, and solvation, as well as backbone motions and side chain fluctuations. The predictions that can be made with this method concerning the roles of ionizable residues for allosteric communication can then be easily tested experimentally by changing the working pH of the protein or performing single point mutations. To demonstrate the method's validity, we have applied this approach to the subtle dynamic regulation mechanism observed for Neisseria meningitidis 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase, the first enzyme of aromatic biosynthesis. We were able to identify key communication pathways linking the allosteric binding site to the active site of the enzyme and to validate these findings experimentally by reestablishing the catalytic activity of allosterically inhibited enzyme via modulation of the working pH, without compromising the binding affinity of the allosteric regulator.
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We examine the dynamic features of non-trivial allosteric binding sites to elucidate potential drug binding sites. These allosteric sites were previously found to be allosteric after determination of the protein-drug co-crystal structure. After comprehensive search in the Protein Data Bank, we identify 10 complex structures with allosteric ligands whose structures are very similar to their functional forms. Then, possible pockets on the protein surface are searched as potential ligand binding sites. To mimic ligand binding to the pocket, complex models are generated to fill out each pocket with pseudo ligand blocks consisting of spheres. Normal mode analysis of the elastic network model is performed for the complex models and unbound structures to assess the change of protein dynamics induced by ligand binding. We examine nine profiles to describe the dynamic and positional characteristics of the pockets, and identify the change of fluctuation around the ligand, ΔMSFbs , as the best profile for distinguishing the allosteric sites from the other sites in 8 structures. These cases should be considered as examples of dynamics-driven allostery, which accompanies significant changes in protein dynamics. ΔMSFbs is suggested to be used for the search of potential dynamics-driven allosteric sites in proteins for drug discovery.
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Initiation of biological processes involving protein–ligand binding, transient protein–protein interactions, or amino acid modifications alters the conformational dynamics of proteins. Accompanying these biological processes are ensuing coupled atomic level conformational changes within the proteins. These conformational changes collectively connect multiple amino acid residues at distal allosteric, binding, and/or active sites. Local changes due to, for example, binding of a regulatory ligand at an allosteric site initiate the allosteric regulation. The allosteric signal propagates throughout the protein structure, causing changes at distal sites, activating, deactivating, or modifying the function of the protein. Hence, dynamical responses within protein structures to stimuli contain critical information on protein function. In this Perspective, we examine the description of allosteric regulation from protein dynamical responses and associated alternative and emerging computational approaches to map allosteric communication pathways between distal sites in proteins at the atomic level.
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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 signal transduction, metabolism, catalysis, and gene regulation. Over recent years, our view and understanding of the fundamental principles underlying allostery have been enriched and often utterly reshaped. This has been especially so for powerful techniques such as nuclear magnetic resonance spectroscopy, which offers an atomic view of the intrinsic motions of proteins. Here, I discuss recent results on the catabolite activator protein (CAP) that have drastically revised our view about how allosteric interactions are modulated. CAP has provided the first experimentally identified system showing that (i) allostery can be mediated through changes in protein motions, in the absence of changes in the mean structure of the protein, and (ii) favorable changes in protein motions may activate allosteric proteins that are otherwise structurally inactive.
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