Allosteric Methods and Their Applications: Facilitating the Discovery of Allosteric Drugs and the Investigation of Allosteric Mechanisms
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ConspectusAllostery, or allosteric regulation, is the phenomenon in which protein functional activity is altered by the binding of an effector at an allosteric site that is topographically distinct from the orthosteric, active site. As one of the most direct and efficient ways to regulate protein function, allostery has played a fundamental role in innumerable biological processes of all living organisms, including enzyme catalysis, signal transduction, cell metabolism, and gene transcription. It is thus considered as "the second secret of life". The abnormality of allosteric communication networks between allosteric and orthosteric sites is associated with the pathogenesis of human diseases. Allosteric modulators, by attaching to structurally diverse allosteric sites, offer the potential for differential selectivity and improved safety compared with orthosteric drugs that bind to conserved orthosteric sites. Harnessing allostery has thus been regarded as a novel strategy for drug discovery.Despite much progress having been made in the repertoire of allostery since the turn of the millennium, the identification of allosteric drugs for therapeutic targets and the elucidation of allosteric mechanisms still present substantial challenges. These challenges are derived from the difficulties in the identification of allosteric sites and mutations, the assessment of allosteric protein–modulator interactions, the screening of allosteric modulators, and the elucidation of allosteric mechanisms in biological systems.To address these issues, we have developed a panel of allosteric services for specific allosteric applications over the past decade, including (i) the creation of the Allosteric Database, with the aim of providing comprehensive allosteric information such as allosteric proteins, modulators, sites, pathways, etc., (ii) the construction of the ASBench benchmark of high-quality allosteric sites for the development of computational methods for predicting allosteric sites, (iii) the development of Allosite and AllositePro for the prediction of the location of allosteric sites in proteins, (iv) the development of the Alloscore scoring function for the evaluation of allosteric protein–modulator interactions, (v) the development of Allosterome for evolutionary analysis of query allosteric sites/modulators within the human proteome, (vi) the development of AlloDriver for the prediction of allosteric mutagenesis, and (vii) the development of AlloFinder for the virtual screening of allosteric modulators and the investigation of allosteric mechanisms. Importantly, we have validated computationally predicted allosteric sites, mutations, and modulators in the real cases of sirtuin 6, casein kinase 2α, phosphodiesterase 10A, and signal transduction and activation of transcription 3. Furthermore, our developed allosteric methods have been widely exploited by other users around the world for allosteric research. Therefore, these allosteric services are expected to expedite the discovery of allosteric drugs and the investigation of allosteric mechanisms.Keywords:
Allosteric enzyme
Allosteric enzyme
Enzyme Catalysis
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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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Allosteric enzyme
Adenosine triphosphate
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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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Allostery is central to many cellular processes, by up- or down-regulating target function. However, what determines the allosteric type remains elusive and currently it is impossible to predict whether the allosteric compounds would activate or inhibit target function before experimental studies. We demonstrated that the allosteric type and allosteric pathways are governed by the forces imposed by ligand binding to target protein using the anisotropic network model and developed an allosteric type prediction method (AlloType). AlloType correctly predicted 13 of the 16 allosteric systems in the data set with experimentally determined protein and complex structures as well as verified allosteric types, which was also used to identify allosteric pathways. When applied to glutathione peroxidase 4, a protein with no complex structure information, AlloType could still be able to predict the allosteric type of the recently reported allosteric activators, demonstrating its potential application in designing specific allosteric drugs and uncovering allosteric mechanisms.
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Allosteric enzyme
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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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Protein Dynamics
Allosteric enzyme
Signaling proteins
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Abstract The effects of activator molecule and repressive molecule on binding process between allosteric enzyme and substrate are discussed by considering the heterotropic effect of the regulating molecule that binds to allosteric enzyme. A model of allosteric enzyme with heterotropic effect is presented. The cooperativity and anticooperativity in the regulation process are studied.
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Adenosine-5'-triphosphate (ATP) is generally regarded as a substrate for energy currency and protein modification. Recent findings uncovered the allosteric function of ATP in cellular signal transduction but little is understood about this critical behavior of ATP. Through extensive analysis of ATP in solution and proteins, we found that the free ATP can exist in the compact and extended conformations in solution, and the two different conformational characteristics may be responsible for ATP to exert distinct biological functions: ATP molecules adopt both compact and extended conformations in the allosteric binding sites but conserve extended conformations in the substrate binding sites. Nudged elastic band simulations unveiled the distinct dynamic processes of ATP binding to the corresponding allosteric and substrate binding sites of uridine monophosphate kinase, and suggested that in solution ATP preferentially binds to the substrate binding sites of proteins. When the ATP molecules occupy the allosteric binding sites, the allosteric trigger from ATP to fuel allosteric communication between allosteric and functional sites is stemmed mainly from the triphosphate part of ATP, with a small number from the adenine part of ATP. Taken together, our results provide overall understanding of ATP allosteric functions responsible for regulation in biological systems.
Allosteric enzyme
Adenosine triphosphate
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Abstract The existence of allosteric phenomena in the control of proteins allows for exquisite control of many of the cell's normal processes. Allosteric interactions involve the binding of an “allosteric” ligand to a site other than the functional (active) site of the protein, with a concomitant alteration in activity. Two major theoretical models have been presented to explain allosteric interactions, that of Monod, Wyman, and Changeux and that of Koshland, Nemethy, Filmer, Dalziel, and Engel. Although there are essential differences between the two models, both require that allosteric ligands interact with one or more forms of the protein to trigger a modulating effect. In only a few cases is much structural detail known about more than one conformational state of any given allosteric protein, or how the binding of small molecule effectors to an allosteric site triggers protein modulation. In this review the essential features of allosteric enzymes and allosteric models are examined in a context that leads to consideration of how drugs may be designed such that they either mimic or block normal allosteric effects. Several existing “allosteric” drugs, and a number of potential targets for the rationale design of future allosteric drugs, are discussed.
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