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Allostery

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Ruth Nussinov – 1st expert on this subject based on the ideXlab platform

  • energetic redistribution in Allostery to execute protein function
    Proceedings of the National Academy of Sciences of the United States of America, 2017
    Co-Authors: Ruth Nussinov

    Abstract:

    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

  • Allostery an overview of its history concepts methods and applications
    PLOS Computational Biology, 2016
    Co-Authors: Ruth Nussinov

    Abstract:

    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.

  • the role of protein loops and linkers in conformational dynamics and Allostery
    Chemical Reviews, 2016
    Co-Authors: Elena Papaleo, Giorgio Saladino, Matteo Lambrughi, Kresten Lindorfflarsen, Francesco Luigi Gervasio, Ruth Nussinov

    Abstract:

    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…

Emily J. Parker – 2nd expert on this subject based on the ideXlab platform

  • Using a Combination of Computational and Experimental Techniques to Understand the Molecular Basis for Protein Allostery
    Advances in Protein Chemistry, 2020
    Co-Authors: Wanting Jiao, Emily J. Parker

    Abstract:

    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.

  • a single amino acid substitution uncouples catalysis and Allostery in an essential biosynthetic enzyme in mycobacterium tuberculosis
    Journal of Biological Chemistry, 2020
    Co-Authors: Wanting Jiao, Emily J. Parker, Nicola J Blackmore

    Abstract:

    : 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.

  • exploring modular Allostery via interchangeable regulatory domains
    Proceedings of the National Academy of Sciences of the United States of America, 2018
    Co-Authors: Penelope J Cross, Emily J. Parker, Geoffrey B Jameson

    Abstract:

    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.

Vincent J Hilser – 3rd expert on this subject based on the ideXlab platform

  • Allostery in its many disguises from theory to applications
    Structure, 2019
    Co-Authors: Shoshana J Wodak, Vincent J Hilser, Jing Li, Emanuele Paci, Nikolay V Dokholyan, Igor N Berezovsky, Amnon Horovitz, Ivet Bahar, John Karanicolas

    Abstract:

    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.

  • Simultaneous Tuning of Activation and Repression in Intrinsic Disorder-Mediated Allostery
    Biophysical Journal, 2016
    Co-Authors: Vincent J Hilser

    Abstract:

    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.

  • Allostery vs allokairy
    Proceedings of the National Academy of Sciences of the United States of America, 2015
    Co-Authors: Vincent J Hilser, James A Anderson, Hesam N Motlagh

    Abstract:

    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.