Allostery in Its Many Disguises: From Theory to Applications

Wodak, Shoshana J.; Paci, Emanuele; Dokholyan, Nikolay V.; Berezovsky, Igor N.; Horovitz, Amnon; Li, Jing; Hilser, Vincent J.; Bahar, İvet; Karanicolas, John; Stock, Gerhard; Hamm, Peter; Stote, Roland H.; Eberhardt, Jérôme; Chebaro, Yassmine; Dejaegere, Annick; Cecchini, Marco; Changeux, Jean Pierre; Bolhuis, Peter G.; Vreede, Jocelyne; Faccioli, Pietro; Orioli, Simone; Ravasio, Riccardo; Yan, Le; Brito, Carolina; Wyart, Matthieu; Gkeka, Paraskevi; Rivalta, Ivan; Palermo, Giulia; McCammon, J. Andrew; Panecka-Hofman, Joanna; Wade, Rebecca C.; Pizio, Antonella Di; Niv, Masha Y.; Nussinov, Ruth; Tsai, Chung Jung; Jang, Hyunbum; Padhorny, Dzmitry; Kozakov, Dima; McLeish, Tom

doi:10.1016/j.str.2019.01.003

Cited by 295 publications

(276 citation statements)

References 122 publications

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“…Although HTS approaches followed by a series of activity tests have proven successful in several cases, in order to fully address the challenge of developing reliable and portable methods of allosteric‐site discovery and allosteric‐ligand design can be even more fully addressed by turning to computational and theoretical approaches. Several excellent reviews and book chapters have already provided very thorough descriptions of methods to study allostery with computational methods, covering approaches rooted in physics, statistics, and sequence analysis …”

Section: Modulating Protein Functions With Allosteric Chemical Switchesmentioning

confidence: 99%

“…ods, covering approaches rooted in physics, statistics, and sequenceanalysis. [6,9,23] Here, we focus on a( personal) selection of recent approaches based on atomistic modeling of targets's tructural dynamics. The study of structurald ynamics combines the fine (atomistic) resolutionr equired by ligand design with the explicit consideration of the functional motions necessary to elicit the formationo f( transient) sites, the communication/ coupling mechanismsb etween distal allosterica nd orthosteric sites, and the common/differential characteristics of an allosteric site among representatives of protein families;i tt hus also paves the way for the design of isoform-selective ligands.…”

Section: Modulating Protein Functions With Allosteric Chemical Switchesmentioning

confidence: 99%

“…Proteins perform their actions by switching between dynamic states and forming new interfaces, favoring the regulation of reactivity and adaptation to different partners in response to varying conditions . The distribution of such dynamic states can be aptly described by the laws of statistical mechanics: the current view involves pre‐existing, well‐defined equilibria between different conformational states and the role of dynamics in facilitating and triggering structural transitions from one state to another . In this model, the activation of specific conformational states that afford the desired functional requirements is brought about by perturbations induced by binding to natural ligands, covalent modification, or binding to one or more partner proteins …”

Section: Introductionmentioning

confidence: 99%

“…[7a] The distribution of such dynamic states can be aptly described by the laws of statistical mechanics:t he current view involvesp re-existing, well-defined equilibria between differentc onformational states and the role of dynamics in facilitating and triggerings tructural transitions from one state to another. [9] In this model, the activation of specific conformational states that afford the desired functional requirements is broughta boutb yp erturbationsi nduced by binding to natural General scheme of how aligand bound inside an allosteric active site (yellow)can induce conformational rearrangements that propagate (orange arrows) throughout its parent protein (cyan), altering the active site (red), as well as different points on its surface (gray) that form potential interfacesf or interaction with other biomolecules. ligands, covalentm odification,o rb inding to one or more partner proteins.…”

Section: Introductionmentioning

confidence: 99%

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Designing Molecular Spanners to Throw in the Protein Networks

Serapian

Colombo

2020

Chemistry A European J

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Proteins govern most aspects of cellular life and, through specific interfaces, are typically involved in intricate protein–protein interaction (PPI) networks and signaling pathways. Subtle up‐ or downregulation of key protein functions and PPIs results in disease; still, the preferred option to contrast the role of a protein in disease and healthy conditions alike remains its outright shutdown through orthosteric ligands that block its active site. Here, we explore subtler alternatives to modulate proteins and PPIs. Driven by a view of proteins as dynamic entities, we discuss ways to identify allosteric binding sites, which, when targeted by tailored ligands, can induce significant changes in the active site of a protein, and lead to agonistic or antagonistic effects. We also summarize the selective regulation of specific PPIs—either direct or allosteric—and show that effects can be stabilizing as well as destabilizing, depending on how the conformational equilibrium of a protein is shifted.

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Section: Modulating Protein Functions With Allosteric Chemical Switchesmentioning

confidence: 99%

Section: Modulating Protein Functions With Allosteric Chemical Switchesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Designing Molecular Spanners to Throw in the Protein Networks

Serapian

Colombo

2020

Chemistry A European J

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“…Allosteric communication is a general mechanism for the regulation of protein function and signalling, because it enables alteration of protein structures at active sites by small changes in a binding pocket several nanometers away. [1][2][3] In spite of its importance as elementary process of cell signalling, there is surprisingly little known about the underlying dynamical process and the timescales of allosteric communication. [4][5][6][7][8][9][10][11] Understanding of the molecular mechanisms of allostery is crucial to, e.g., elucidate the effects of point mutations in cancer development 12 and exploit it for the design of small molecule drugs.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Wolf

Sohmen

Hellenkamp

et al. 2020

Preprint

Self Cite

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I.ABSTRACTSeveral indicators for a signal propagation from a binding site to a distant functional site have been found in the Hsp90 dimer. Here we determined a time-resolved pathway from ATP hydrolysis to changes in a distant folding substrate binding site. This was possible by combining single-molecule fluorescence-based methods with extensive atomistic nonequilibrium molecular dynamics simulations. We find that hydrolysis of one ATP effects a structural asymmetry in the full Hsp90 dimer that leads to the collapse of a central folding substrate binding site. Arg380 is the major mediator in transferring structural information from the nucleotide to the substrate binding site. This allosteric process occurs via hierarchical dynamics that involve timescales from picoto milliseconds and length scales from Ångstroms to several nanometers. We presume that similar hierarchical mechanisms are fundamental for information transfer through many other proteins.

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Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

Kim

Jung

et al. 2023

Advanced Materials

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transduction to enable survival and adaption. They are composed of long folded chains made up of a variety of 20 different α-amino acids, which form elaborate molecular structures. These structures can then fit counterpart molecules via molecular complementarity, thus enabling them to perform their specific cellular functions (Figure 1). For instance, membrane receptors specifically recognize extracellular ligand molecules and transfer desired molecular signals into the cell across the ligand-impermeable membrane. [1][2][3] Moreover, different membrane channels exist at the cell surface; in response to external stimuli such as pH, temperature, and action potentials, they undergo conformational changes to modulate the permeability of specific ions and metabolites. [4][5][6] The received extracellular signals are then converted into appropriate cellular responses; this process involves the intracellular increase of certain molecules to control transcription factors and regulate gene expression. [7,8] Even within the cell, there are various proteinligand interactions; for example, some metabolites can bind transcription factors, allosterically regulating subsequent transcription by RNA polymerases. [9,10] To manage cellular metabolism, enzymes catalyze more than 5000 biochemical reactions under highly limited physiological conditions (e.g., mild temperature, neutral pH, and low salt concentrations), attributed to their specific substrate binding abilities and effective collaboration with cofactors or coenzymes. [11] The availability of proteins that interact with many different targets benefits a broad range of biological and biotechnological research. Due to the functional diversity and specificity of the proteins, synthetic biology has successfully refined and rewired various cellular functions to solve numerous issues in a diverse range of fields such as agriculture, [12] manufacturing, [13] pharmaceutics, [14] and therapeutics. [15,16] For example, the use of proteins that enable gene recognition and editing has contributed to the emergence of important metabolic and genetic engineering techniques, allowing for the modulation of microbial cell factories that can efficiently produce high-value products, including biofuels, [17] medicines, [14] and biomolecules for industrial use. [18] Moreover, genetically encoded signal transducers As biomolecules essential for sustaining life, proteins are generated from long chains of 20 different α-amino acids that are folded into unique 3D structures. In particular, many proteins have molecular recognition functions owing to their binding pockets, which have complementary shapes, charges, and polarities for specific targets, making these biopolymers unique and highly valuable for biomedical and biocatalytic applications. Based on the understanding of protein structures and microenvironments, molecular complementarity can be exhibited by synthesizable and modifiable materials. This has prompted researchers to explore the proteomimetic potentials of a diverse range of material...

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Allostery in Its Many Disguises: From Theory to Applications

Cited by 295 publications

References 122 publications

Designing Molecular Spanners to Throw in the Protein Networks

Designing Molecular Spanners to Throw in the Protein Networks

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

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