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Journal articles on the topic 'Allosteric regulation'

Author: Grafiati

Published: 4 June 2021

Last updated: 25 May 2024

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1

Leander, Megan, Yuchen Yuan, Anthony Meger, Qiang Cui, and Srivatsan Raman. "Functional plasticity and evolutionary adaptation of allosteric regulation." Proceedings of the National Academy of Sciences 117, no. 41 (September 30, 2020): 25445–54. http://dx.doi.org/10.1073/pnas.2002613117.

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Allostery is a fundamental regulatory mechanism of protein function. Despite notable advances, understanding the molecular determinants of allostery remains an elusive goal. Our current knowledge of allostery is principally shaped by a structure-centric view, which makes it difficult to understand the decentralized character of allostery. We present a function-centric approach using deep mutational scanning to elucidate the molecular basis and underlying functional landscape of allostery. We show that allosteric signaling exhibits a high degree of functional plasticity and redundancy through myriad mutational pathways. Residues critical for allosteric signaling are surprisingly poorly conserved while those required for structural integrity are highly conserved, suggesting evolutionary pressure to preserve fold over function. Our results suggest multiple solutions to the thermodynamic conditions of cooperativity, in contrast to the common view of a finely tuned allosteric residue network maintained under selection.

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2

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 (May 7, 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 underlying allosteric regulation from these data. Markov state models are one of the most promising methods for this purpose. We provide a short introduction to the theory of Markov state models and review their application to various examples of protein allostery studied by MD simulations. We also include a discussion of studies where Markov modelling has been employed to analyse experimental data on allosteric regulation. We conclude our review by advertising the wider application of Markov state models to elucidate allosteric mechanisms, especially since in recent years it has become straightforward to construct such models thanks to software programs like PyEMMA and MSMBuilder. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.

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3

Motlagh, Hesam N., Jing Li, E. Brad Thompson, and Vincent J. Hilser. "Interplay between allostery and intrinsic disorder in an ensemble." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 975–80. http://dx.doi.org/10.1042/bst20120163.

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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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4

Abrusán, György, David B. Ascher, and Michael Inouye. "Known allosteric proteins have central roles in genetic disease." PLOS Computational Biology 18, no. 2 (February 9, 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 an association between being allosteric and involvement in disease; 2) they are enriched in many major disease types like hematopoietic diseases, cardiovascular diseases, cancers, diabetes, or diseases of the central nervous system; 3) variants from cancer genome-wide association studies are enriched near allosteric proteins, indicating their importance to polygenic traits; and 4) the importance of allosteric proteins in disease is due, at least partly, to their central positions in protein-protein interaction networks, and less due to their dynamical properties.

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5

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 (October 26, 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 validation of allosteric ligands.

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6

Hadzipasic, Adelajda, Christopher Wilson, Vy Nguyen, Nadja Kern, Chansik Kim, Warintra Pitsawong, Janice Villali, Yuejiao Zheng, and Dorothee Kern. "Ancient origins of allosteric activation in a Ser-Thr kinase." Science 367, no. 6480 (February 20, 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-associated protein TPX2 appeared, efficient kinase binding to TPX2 evolved, likely owing to increased fitness by virtue of colocalization. Subsequently, TPX2-mediated allosteric kinase regulation gradually evolved. Surprisingly, evolution of this regulation is encoded in the kinase and did not arise by a dominating mechanism of coevolution.

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7

Vinkenborg, Jan L., Nora Karnowski, and Michael Famulok. "Aptamers for allosteric regulation." Nature Chemical Biology 7, no. 8 (July 18, 2011): 519–27. http://dx.doi.org/10.1038/nchembio.609.

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8

VanHook, Annalisa M. "Allosteric regulation of Warts." Science Signaling 9, no. 409 (January 5, 2016): ec2-ec2. http://dx.doi.org/10.1126/scisignal.aaf1721.

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9

Horovitz, Amnon, and Keith R. Willison. "Allosteric regulation of chaperonins." Current Opinion in Structural Biology 15, no. 6 (December 2005): 646–51. http://dx.doi.org/10.1016/j.sbi.2005.10.001.

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10

Biswas, Kabir H. "Allosteric regulation of proteins." Resonance 22, no. 1 (January 2017): 37–50. http://dx.doi.org/10.1007/s12045-017-0431-z.

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11

Gold, Vicki A. M., Alice Robson, Anthony R. Clarke, and Ian Collinson. "Allosteric Regulation of SecA." Journal of Biological Chemistry 282, no. 24 (April 6, 2007): 17424–32. http://dx.doi.org/10.1074/jbc.m702066200.

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12

Hauske, Patrick, Christian Ottmann, Michael Meltzer, Michael Ehrmann, and Markus Kaiser. "Allosteric Regulation of Proteases." ChemBioChem 9, no. 18 (December 15, 2008): 2920–28. http://dx.doi.org/10.1002/cbic.200800528.

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13

Kneuttinger, Andrea C., Stefanie Zwisele, Kristina Straub, Astrid Bruckmann, Florian Busch, Thomas Kinateder, Barbara Gaim, Vicki H. Wysocki, Rainer Merkl, and Reinhard Sterner. "Light-Regulation of Tryptophan Synthase by Combining Protein Design and Enzymology." International Journal of Molecular Sciences 20, no. 20 (October 15, 2019): 5106. http://dx.doi.org/10.3390/ijms20205106.

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The spatiotemporal control of enzymes by light is of growing importance for industrial biocatalysis. Within this context, the photo-control of allosteric interactions in enzyme complexes, common to practically all metabolic pathways, is particularly relevant. A prominent example of a metabolic complex with a high application potential is tryptophan synthase from Salmonella typhimurium (TS), in which the constituting TrpA and TrpB subunits mutually stimulate each other via a sophisticated allosteric network. To control TS allostery with light, we incorporated the unnatural amino acid o-nitrobenzyl-O-tyrosine (ONBY) at seven strategic positions of TrpA and TrpB. Initial screening experiments showed that ONBY in position 58 of TrpA (aL58ONBY) inhibits TS activity most effectively. Upon UV irradiation, ONBY decages to tyrosine, largely restoring the capacity of TS. Biochemical characterization, extensive steady-state enzyme kinetics, and titration studies uncovered the impact of aL58ONBY on the activities of TrpA and TrpB and identified reaction conditions under which the influence of ONBY decaging on allostery reaches its full potential. By applying those optimal conditions, we succeeded to directly light-activate TS(aL58ONBY) by a factor of ~100. Our findings show that rational protein design with a photo-sensitive unnatural amino acid combined with extensive enzymology is a powerful tool to fine-tune allosteric light-activation of a central metabolic enzyme complex.

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14

Davidovich, Chen, and Qi Zhang. "Allosteric regulation of histone lysine methyltransferases: from context-specific regulation to selective drugs." Biochemical Society Transactions 49, no. 2 (March 26, 2021): 591–607. http://dx.doi.org/10.1042/bst20200238.

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Histone lysine methyltransferases (HKMTs) are key regulators of many cellular processes. By definition, HKMTs catalyse the methylation of lysine residues in histone proteins. The enzymatic activities of HKMTs are under precise control, with their allosteric regulation emerging as a prevalent paradigm. We review the molecular mechanisms of allosteric regulation of HKMTs using well-studied histone H3 (K4, K9, K27 and K36) methyltransferases as examples. We discuss the current advances and future potential in targeting allosteric sites of HKMTs for drug development.

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15

Faustova, Ilona, Aleksei Kuznetsov, Erkki Juronen, Mart Loog, and Jaak Järv. "Phosphorylation is switch of L-type pyruvate kinase allostery." Open Life Sciences 5, no. 2 (April 1, 2010): 135–42. http://dx.doi.org/10.2478/s11535-010-0004-6.

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AbstractAmong four pyruvate kinase isoenzymes, M1, M2, R and L, only M1 is considered as a nonallosteric enzyme. However, here we show that the non-phosphorylated L-type pyruvate kinase (L-PK) is also a non-allosteric enzyme with respect to its substrate phosphoenolpyruvate (PEP). The allosteric catalytic properties of L-PK are switched on through phosphorylation by cAMP-dependent protein kinase. The non-phosphorylated enzyme was produced by expressing the rat L-PK in E. coli, as the bacterium does not have mammalian-type protein kinases. The resulting tetrameric protein was phosphorylated with a stoichiometric ratio of one mole of phosphate per one L-PK monomer. Activity of the phosphorylated enzyme was allosterically regulated by PEP with the Hill coefficient n=2.5. It was observed that allostery was engaged by phosphorylation of the first subunit in the tetrameric enzyme, while further phosphorylation only modulated this effect. The discovered switching between non-allosteric and allosteric forms of L-PK and the possibility of modulating the allostery by phosphorylation are important for understanding of the interrelationship between allostery and the regulatory phosphorylation in general, and may have implication for further analysis of glycolysis regulation in the liver.

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16

Verkhivker, Gennady, Mohammed Alshahrani, Grace Gupta, Sian Xiao, and Peng Tao. "From Deep Mutational Mapping of Allosteric Protein Landscapes to Deep Learning of Allostery and Hidden Allosteric Sites: Zooming in on “Allosteric Intersection” of Biochemical and Big Data Approaches." International Journal of Molecular Sciences 24, no. 9 (April 24, 2023): 7747. http://dx.doi.org/10.3390/ijms24097747.

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The recent advances in artificial intelligence (AI) and machine learning have driven the design of new expert systems and automated workflows that are able to model complex chemical and biological phenomena. In recent years, machine learning approaches have been developed and actively deployed to facilitate computational and experimental studies of protein dynamics and allosteric mechanisms. In this review, we discuss in detail new developments along two major directions of allosteric research through the lens of data-intensive biochemical approaches and AI-based computational methods. Despite considerable progress in applications of AI methods for protein structure and dynamics studies, the intersection between allosteric regulation, the emerging structural biology technologies and AI approaches remains largely unexplored, calling for the development of AI-augmented integrative structural biology. In this review, we focus on the latest remarkable progress in deep high-throughput mining and comprehensive mapping of allosteric protein landscapes and allosteric regulatory mechanisms as well as on the new developments in AI methods for prediction and characterization of allosteric binding sites on the proteome level. We also discuss new AI-augmented structural biology approaches that expand our knowledge of the universe of protein dynamics and allostery. We conclude with an outlook and highlight the importance of developing an open science infrastructure for machine learning studies of allosteric regulation and validation of computational approaches using integrative studies of allosteric mechanisms. The development of community-accessible tools that uniquely leverage the existing experimental and simulation knowledgebase to enable interrogation of the allosteric functions can provide a much-needed boost to further innovation and integration of experimental and computational technologies empowered by booming AI field.

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17

White, Jordan T., Jing Li, Emily Grasso, James O. Wrabl, and Vincent J. Hilser. "Ensemble allosteric model: energetic frustration within the intrinsically disordered glucocorticoid receptor." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1749 (May 7, 2018): 20170175. http://dx.doi.org/10.1098/rstb.2017.0175.

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Allostery is an important regulatory phenomenon enabling precise control of biological function. Initial understanding of allostery was gained from seminal work on conformational changes exhibited by structured proteins. Within the last decade, protein allostery has also been demonstrated to occur within intrinsically disordered proteins. This emerging concept of disorder-mediated allostery can be usefully understood in the context of a thermodynamic ensemble. The advantage of this ensemble allosteric model is that it unifies the explanations of allostery occurring within both structured and disordered proteins. One central finding from this model is that energetic coupling, the transmission of a signal between separate regions (or domains) of a protein, is maximized when one or more domains are disordered. This is due to a disorder–order transition that contributes additional coupling energy to the allosteric system through formation of a molecular interaction surface or interface. A second key finding is that multiple interfaces may constructively or destructively interfere with each other, resulting in a new form of allosteric regulation called ‘energetic frustration’. Articulating protein allostery in terms of the thermodynamic ensemble permits formulation of experimentally testable hypotheses which can increase fundamental understanding and direct drug-design efforts. These ideas are illustrated here with the specific case of human glucocorticoid receptor, a medically important multi-domain allosteric protein that contains both structured and disordered regions and exemplifies ‘energetic frustration’. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.

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18

Coffino, Philip, and Yifan Cheng. "Allostery Modulates Interactions between Proteasome Core Particles and Regulatory Particles." Biomolecules 12, no. 6 (May 30, 2022): 764. http://dx.doi.org/10.3390/biom12060764.

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Allostery—regulation at distant sites is a key concept in biology. The proteasome exhibits multiple forms of allosteric regulation. This regulatory communication can span a distance exceeding 100 Ångstroms and can modulate interactions between the two major proteasome modules: its core particle and regulatory complexes. Allostery can further influence the assembly of the core particle with regulatory particles. In this focused review, known and postulated interactions between these proteasome modules are described. Allostery may explain how cells build and maintain diverse populations of proteasome assemblies and can provide opportunities for therapeutic interventions.

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19

Liang, Zhongjie, Gennady M. Verkhivker, and Guang Hu. "Integration of network models and evolutionary analysis into high-throughput modeling of protein dynamics and allosteric regulation: theory, tools and applications." Briefings in Bioinformatics 21, no. 3 (March 21, 2019): 815–35. http://dx.doi.org/10.1093/bib/bbz029.

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Abstract Proteins are dynamical entities that undergo a plethora of conformational changes, accomplishing their biological functions. Molecular dynamics simulation and normal mode analysis methods have become the gold standard for studying protein dynamics, analyzing molecular mechanism and allosteric regulation of biological systems. The enormous amount of the ensemble-based experimental and computational data on protein structure and dynamics has presented a major challenge for the high-throughput modeling of protein regulation and molecular mechanisms. In parallel, bioinformatics and systems biology approaches including genomic analysis, coevolution and network-based modeling have provided an array of powerful tools that complemented and enriched biophysical insights by enabling high-throughput analysis of biological data and dissection of global molecular signatures underlying mechanisms of protein function and interactions in the cellular environment. These developments have provided a powerful interdisciplinary framework for quantifying the relationships between protein dynamics and allosteric regulation, allowing for high-throughput modeling and engineering of molecular mechanisms. Here, we review fundamental advances in protein dynamics, network theory and coevolutionary analysis that have provided foundation for rapidly growing computational tools for modeling of allosteric regulation. We discuss recent developments in these interdisciplinary areas bridging computational biophysics and network biology, focusing on promising applications in allosteric regulations, including the investigation of allosteric communication pathways, protein–DNA/RNA interactions and disease mutations in genomic medicine. We conclude by formulating and discussing future directions and potential challenges facing quantitative computational investigations of allosteric regulatory mechanisms in protein systems.

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20

Jiao, Wanting. "Computational investigations of allostery in aromatic amino acid biosynthetic enzymes." Biochemical Society Transactions 49, no. 1 (February 5, 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 allostery. The aromatic amino acid biosynthesis pathway is essential in microorganisms and plants. Multiple enzymes involved in this pathway are sensitive to feedback regulation by pathway end products and are known to use allostery to control their activities. To date, four enzymes in the aromatic amino acid biosynthesis pathway have been computationally investigated for their allosteric mechanisms, including 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase, anthranilate synthase, chorismate mutase, and tryptophan synthase. Here we review the computational studies and findings on the allosteric mechanisms of these four enzymes. Results from these studies demonstrate the capability of computational tools and encourage future computational investigations of allostery in other enzymes of this pathway.

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21

Shpakov, Alexander O. "Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands." International Journal of Molecular Sciences 24, no. 7 (March 24, 2023): 6187. http://dx.doi.org/10.3390/ijms24076187.

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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22

Fan, Yifei, Penelope J. Cross, Geoffrey B. Jameson, and Emily J. Parker. "Exploring modular allostery via interchangeable regulatory domains." Proceedings of the National Academy of Sciences 115, no. 12 (March 5, 2018): 3006–11. http://dx.doi.org/10.1073/pnas.1717621115.

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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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23

Buchenberg, Sebastian, Florian Sittel, and Gerhard Stock. "Time-resolved observation of protein allosteric communication." Proceedings of the National Academy of Sciences 114, no. 33 (July 31, 2017): E6804—E6811. http://dx.doi.org/10.1073/pnas.1707694114.

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Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales. Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication in PDZ2S is developed. The simulations reveal that allostery amounts to the propagation of structural and dynamical changes that are genuinely nonlinear and can occur in a nonlocal fashion. A dynamic network model is constructed that illustrates the hierarchy and exceeding structural heterogeneity of the process. In compelling agreement with experiment, three physically distinct phases of the time evolution are identified, describing elastic response (≲0.1 ns), inelastic reorganization (∼100 ns), and structural relaxation (≳1μs). Issues such as the similarity to downhill folding as well as the interpretation of allosteric pathways are discussed.

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24

AKIYAMA, Masashi. "Allosteric regulation of ADAMTS13 activity." Japanese Journal of Thrombosis and Hemostasis 33, no. 4 (2022): 394–98. http://dx.doi.org/10.2491/jjsth.33.394.

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25

Keller, Evelyn Fox. "Doing justice to allosteric regulation." Comptes Rendus Biologies 338, no. 6 (June 2015): 385–90. http://dx.doi.org/10.1016/j.crvi.2015.03.009.

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Hoffpauir, Zoe A., Eleena Sherman, Hong Q. Smith, and Thomas J. Smith. "Allosteric Regulation of Glutamate Dehydrogenase." Biophysical Journal 118, no. 3 (February 2020): 533a. http://dx.doi.org/10.1016/j.bpj.2019.11.2923.

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27

Fitzpatrick, Paul F. "Allosteric regulation of phenylalanine hydroxylase." Archives of Biochemistry and Biophysics 519, no. 2 (March 2012): 194–201. http://dx.doi.org/10.1016/j.abb.2011.09.012.

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Astore, Miro A., Akshada S. Pradhan, Erik H. Thiede, and Sonya M. Hanson. "Protein dynamics underlying allosteric regulation." Current Opinion in Structural Biology 84 (February 2024): 102768. http://dx.doi.org/10.1016/j.sbi.2023.102768.

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29

Suplatov, D. А., and V. К. Švedas. "Study of Functional and Allosteric Sites in Protein Superfamilies." Acta Naturae 7, no. 4 (December 15, 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. Novel approaches are needed to systematically analyze the architecture and role of various binding sites and establish the relationship between structure, function, and regulation. Computational biology, bioinformatics, and molecular modeling can be used to search for new regulatory centers, characterize their structural peculiarities, as well as compare different pockets in homologous proteins, study the molecular mechanisms of allostery, and understand the communication between topologically independent binding sites in protein structures. The establishment of an evolutionary relationship between different binding centers within protein superfamilies and the discovery of new functional and allosteric (regulatory) sites using computational approaches can improve our understanding of the structure-function relationship in proteins and provide new opportunities for drug design and enzyme engineering.

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30

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 (March 15, 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 of the common and distinctive features of the structural organization of both functional (catalytic) and allosteric sites, the evolution of their amino acid sequences in respective protein families, and allosteric communication pathways. The CASBench benchmark set contains 91 entries related to enzymes with both catalytic and allosteric sites within their structures annotated based on the experimental information from the Allosteric Database, Catalytic Site Atlas, and Protein Data Bank. The obtained dataset can be used to benchmark the performance of existing computational approaches and develop/train perspective algorithms to search for new catalytic and regulatory sites, as well as to study the mechanisms of protein regulation on a large collection of allosteric enzymes. Establishing a relationship between the structure, function, and regulation is expected to improve our understanding of the mechanisms of action of enzymes and open up new prospects for discovering new drugs and designing more efficient biocatalysts. The CASBench can be operated offline on a local computer or online using built-in interactive tools at https://biokinet.belozersky.msu.ru/casbench.

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Helmstaedt, Kerstin, Sven Krappmann, and Gerhard H. Braus. "Allosteric Regulation of Catalytic Activity:Escherichia coli Aspartate Transcarbamoylase versus Yeast Chorismate Mutase." Microbiology and Molecular Biology Reviews 65, no. 3 (September 1, 2001): 404–21. http://dx.doi.org/10.1128/mmbr.65.3.404-421.2001.

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SUMMARY Allosteric regulation of key metabolic enzymes is a fascinating field to study the structure-function relationship of induced conformational changes of proteins. In this review we compare the principles of allosteric transitions of the complex classical model aspartate transcarbamoylase (ATCase) from Escherichia coli, consisting of 12 polypeptides, and the less complicated chorismate mutase derived from baker's yeast, which functions as a homodimer. Chorismate mutase presumably represents the minimal oligomerization state of a cooperative enzyme which still can be either activated or inhibited by different heterotropic effectors. Detailed knowledge of the number of possible quaternary states and a description of molecular triggers for conformational changes of model enzymes such as ATCase and chorismate mutase shed more and more light on allostery as an important regulatory mechanism of any living cell. The comparison of wild-type and engineered mutant enzymes reveals that current textbook models for regulation do not cover the entire picture needed to describe the function of these enzymes in detail.

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32

Freedman, Robert B., and Alan D. B. Malcolm. "Allosteric regulation: Illuminating allosteric conformational change with an environmentally sensitive fluorescent probe." Biochemist 37, no. 3 (June 1, 2015): 54–57. http://dx.doi.org/10.1042/bio03703054.

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Allosteric regulation was a hot topic in the 1960s, but there was very limited structural data on allosteric equilibria, and no solid information on the rates of allosteric conformational changes. In this Biochemical Journal Classic paper from 1969 George Radda and his first D.Phil. student, George Dodd determined the rate of allosteric transition in the regulatory enzyme glutamate dehydrogenase by a method new in the 1960s, the fluorescence of an environmentally sensitive extrinsic probe.

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Arutyunova, Elena, Pankaj Panwar, Pauline M. Skiba, Nicola Gale, Michelle W. Mak, and M. Joanne Lemieux. "Allosteric regulation of rhomboid intramembrane proteolysis." EMBO Journal 33, no. 17 (July 9, 2014): 1869–81. http://dx.doi.org/10.15252/embj.201488149.

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Valentini, Giovanna, Laurent Chiarelli, Riccardo Fortin, Maria L. Speranza, Alessandro Galizzi, and Andrea Mattevi. "The Allosteric Regulation of Pyruvate Kinase." Journal of Biological Chemistry 275, no. 24 (April 4, 2000): 18145–52. http://dx.doi.org/10.1074/jbc.m001870200.

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Chung, Dominic W. "Hairpin and allosteric regulation in ADAMTS13." Blood 133, no. 17 (April 25, 2019): 1800–1801. http://dx.doi.org/10.1182/blood-2019-02-900563.

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Pincus, David, Jai P. Pandey, Zoë A. Feder, Pau Creixell, Orna Resnekov, and Kimberly A. Reynolds. "Engineering allosteric regulation in protein kinases." Science Signaling 11, no. 555 (November 6, 2018): eaar3250. http://dx.doi.org/10.1126/scisignal.aar3250.

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Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed “hotspots” that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consensus phosphorylation sites at these hotspots, we rewired cell signaling in yeast. Using the same approach with a homolog yeast mitogen-activated protein kinase, Hog1, we introduced new phosphoregulation that modified its localization and signaling dynamics. Beyond revealing potential use in synthetic biology, our findings suggest that the identified hotspots contribute to the diversity of natural allosteric regulatory mechanisms in the eukaryotic kinome and, given that some are mutated in cancers, understanding these hotspots may have clinical relevance to human disease.

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Kim, Jung-Ae, Minjung Kwon, and Jaehoon Kim. "Allosteric Regulation of Chromatin-Modifying Enzymes." Biochemistry 58, no. 1 (October 17, 2018): 15–23. http://dx.doi.org/10.1021/acs.biochem.8b00894.

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Puzicha, Gisbert, Yu Ming Pu, and David A. Lightner. "Allosteric regulation of conformational enantiomerism. Bilirubin." Journal of the American Chemical Society 113, no. 9 (April 1991): 3583–92. http://dx.doi.org/10.1021/ja00009a055.

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Merdanovic, Melisa, Timon Mönig, Michael Ehrmann, and Markus Kaiser. "Diversity of Allosteric Regulation in Proteases." ACS Chemical Biology 8, no. 1 (December 3, 2012): 19–26. http://dx.doi.org/10.1021/cb3005935.

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Zucconi, Beth E., and Philip A. Cole. "Allosteric regulation of epigenetic modifying enzymes." Current Opinion in Chemical Biology 39 (August 2017): 109–15. http://dx.doi.org/10.1016/j.cbpa.2017.05.015.

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Goldbeter, Albert, and Geneviève Dupont. "Allosteric regulation, cooperativity, and biochemical oscillations." Biophysical Chemistry 37, no. 1-3 (August 1990): 341–53. http://dx.doi.org/10.1016/0301-4622(90)88033-o.

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Shashikanth, Nitesh, Yuliya I. Petrova, Seongjin Park, Jillian Chekan, Stephanie Maiden, Martha Spano, Taekjip Ha, Barry M. Gumbiner, and Deborah E. Leckband. "Allosteric Regulation of E-Cadherin Adhesion." Journal of Biological Chemistry 290, no. 35 (July 14, 2015): 21749–61. http://dx.doi.org/10.1074/jbc.m115.657098.

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Subramanian, Chitra, Mi-Kyung Yun, Jiangwei Yao, Lalit Kumar Sharma, Richard E. Lee, Stephen W. White, Suzanne Jackowski, and Charles O. Rock. "Allosteric Regulation of Mammalian Pantothenate Kinase." Journal of Biological Chemistry 291, no. 42 (August 23, 2016): 22302–14. http://dx.doi.org/10.1074/jbc.m116.748061.

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Ropp, Patricia A., and Thomas W. Traut. "Allosteric regulation of purine nucleoside phosphorylase." Archives of Biochemistry and Biophysics 288, no. 2 (August 1991): 614–20. http://dx.doi.org/10.1016/0003-9861(91)90244-d.

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Wang, Yuhang, Abhi Singharoy, Klaus Schulten, and Emad Tajkhorshid. "Allosteric Regulation Mechanism of Trimeric Membrane." Biophysical Journal 110, no. 3 (February 2016): 383a. http://dx.doi.org/10.1016/j.bpj.2015.11.2069.

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Fastrez, Jacques. "Engineering Allosteric Regulation into Biological Catalysts." ChemBioChem 10, no. 18 (December 14, 2009): 2824–35. http://dx.doi.org/10.1002/cbic.200900590.

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Mattevi, Andrea, Martino Bolognesi, and Giovanna Valentini. "The allosteric regulation of pyruvate kinase." FEBS Letters 389, no. 1 (June 24, 1996): 15–19. http://dx.doi.org/10.1016/0014-5793(96)00462-0.

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Lechtenberg, Bernhard C., Stefan M. V. Freund, and James A. Huntington. "An ensemble view of thrombin allostery." Biological Chemistry 393, no. 9 (September 1, 2012): 889–98. http://dx.doi.org/10.1515/hsz-2012-0178.

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Abstract Thrombin is the central protease of the coagulation cascade. Its activity is tightly regulated to ensure rapid blood clotting while preventing uncontrolled thrombosis. Thrombin interacts with multiple substrates and cofactors and is critically involved in both pro- and anticoagulant pathways of the coagulation network. Its allosteric regulation, especially by the monovalent cation Na+, has been the focus of research for more than 30 years. It is believed that thrombin can adopt an anticoagulant (‘slow’) conformation and, after Na+ binding, a structurally distinct procoagulant (‘fast’) state. In the past few years, however, the general view of allostery has evolved from one of rigid structural changes towards thermodynamic ensembles of conformational states. With this background, the view of the allosteric regulation of thrombin has also changed. The static view of the two-state model has been dismissed in favor of a more dynamic view of thrombin allostery. Herein, we review recent data that demonstrate that apo-thrombin is zymogen-like and exists as an ensemble of conformations. Furthermore, we describe how ligand binding to thrombin allosterically stabilizes conformations on the continuum from zymogen to protease.

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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 (March 27, 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 motions and concerted slower motions. Allosterically impaired CzrA mutants are characterized by distinct nonnative fast internal dynamics “fingerprints” upon Zn binding, and DNA binding is weakly regulated. We demonstrate the predictive power of the wild-type dynamics fingerprint to identify key residues in dynamics-driven allostery. We propose that driving forces arising from dynamics can be harnessed by nature to evolve new allosteric ligand specificities in a compact molecular scaffold.

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Glenn, Katie, and Kerry S. Smith. "Allosteric Regulation of Lactobacillus plantarum Xylulose 5-Phosphate/Fructose 6-Phosphate Phosphoketolase (Xfp)." Journal of Bacteriology 197, no. 7 (January 20, 2015): 1157–63. http://dx.doi.org/10.1128/jb.02380-14.

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ABSTRACTXylulose 5-phosphate/fructose 6-phosphate phosphoketolase (Xfp), which catalyzes the conversion of xylulose 5-phosphate (X5P) or fructose 6-phosphate (F6P) to acetyl phosphate, plays a key role in carbohydrate metabolism in a number of bacteria. Recently, we demonstrated that the fungalCryptococcus neoformansXfp2 exhibits both substrate cooperativity for all substrates (X5P, F6P, and Pi) and allosteric regulation in the forms of inhibition by phosphoenolpyruvate (PEP), oxaloacetic acid (OAA), and ATP and activation by AMP (K. Glenn, C. Ingram-Smith, and K. S. Smith. Eukaryot Cell13:657–663, 2014). Allosteric regulation has not been reported previously for the characterized bacterial Xfps. Here, we report the discovery of substrate cooperativity and allosteric regulation among bacterial Xfps, specifically theLactobacillus plantarumXfp.L. plantarumXfp is an allosteric enzyme inhibited by PEP, OAA, and glyoxylate but unaffected by the presence of ATP or AMP. Glyoxylate is an additional inhibitor to those previously reported forC. neoformansXfp2. As withC. neoformansXfp2, PEP and OAA share the same or possess overlapping sites onL. plantarumXfp. Glyoxylate, which had the lowest half-maximal inhibitory concentration of the three inhibitors, binds at a separate site. This study demonstrates that substrate cooperativity and allosteric regulation may be common properties among bacterial and eukaryotic Xfp enzymes, yet important differences exist between the enzymes in these two domains.IMPORTANCEXylulose 5-phosphate/fructose 6-phosphate phosphoketolase (Xfp) plays a key role in carbohydrate metabolism in a number of bacteria. Although we recently demonstrated that the fungalCryptococcusXfp is subject to substrate cooperativity and allosteric regulation, neither phenomenon has been reported for a bacterial Xfp. Here, we report that theLactobacillus plantarumXfp displays substrate cooperativity and is allosterically inhibited by phosphoenolpyruvate and oxaloacetate, as is the case forCryptococcusXfp. The bacterial enzyme is unaffected by the presence of AMP or ATP, which act as a potent activator and inhibitor of the fungal Xfp, respectively. Our results demonstrate that substrate cooperativity and allosteric regulation may be common properties among bacterial and eukaryotic Xfps, yet important differences exist between the enzymes in these two domains.

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