Protein conformational switch discerned via network centrality properties

Foutch, David; Pham, Bill; Shen, Tongye

doi:10.1016/j.csbj.2021.06.004

Cited by 30 publications

(28 citation statements)

References 59 publications

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“…A multitude of advanced MD simulation software packages and algorithms have been developed for different applications. Classical large-scale unbiased MD simulations can sample a wide range of protein dynamic conformation ensembles at the atomic scale to discover intermediate states. , Accelerated MD simulations facilitate conformational changes in protein complexes with slow time scale dynamics by introducing a non-negative boost potential. , Collectively, simulation-based approaches can detect the reversed allosteric effect of allosteric proteins at both spatial and temporal scales.…”

Section: Methodologies For Reversed Allosteric Communication Investig...mentioning

confidence: 99%

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

et al. 2021

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Allostery is a fundamental and extensive mechanism of intramolecular signal transmission. Allosteric drugs possess several unique pharmacological advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity. However, owing to the complexity of allosteric regulation, experimental approaches for the development of allosteric modulators are traditionally serendipitous. Recently, the reversed allosteric communication theory has been proposed, providing a feasible tool for the unbiased detection of allosteric sites. Herein, we review the latest research on the reversed allosteric communication effect using the examples of sirtuin 6, epidermal growth factor receptor, 3-phosphoinositide-dependent protein kinase 1, and Related to A and C kinases (RAC) serine/threonine protein kinase B and recapitulate the methodologies of reversed allosteric communication strategy. The novel reversed allosteric communication strategy greatly expands the horizon of allosteric site identification and allosteric mechanism exploration and is expected to accelerate an end-to-end framework for drug discovery.

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Section: Methodologies For Reversed Allosteric Communication Investig...mentioning

confidence: 99%

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

et al. 2021

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“…The whole simulated trajectories were selected for community network analysis. The two Cα atoms within a cut-off distance of 4.5 Å that has an occupation time >75% of simulation time were classified into the same community ( Sethi et al, 2009 ; Liang et al, 2020 ; Li et al, 2021a ; Foutch et al, 2021 ; Tian et al, 2021 ). Each community was represented by coloured circles whose size is related to the number of residues it includes.…”

Section: Resultsmentioning

confidence: 99%

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Liu

et al. 2022

Front. Mol. Biosci.

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As a member of the death-associated protein kinase family of serine/threonine kinases, the STK17B has been associated with diverse diseases such as hepatocellular carcinoma. However, the conformational dynamics of the phosphate-binding loop (P-loop) in the determination of inhibitor selectivity profile to the STK17B are less understood. Here, a multi-microsecond length molecular dynamics (MD) simulation of STK17B in the three different states (ligand-free, ADP-bound, and ligand-bound states) was carried out to uncover the conformational plasticity of the P-loop. Together with the analyses of principal component analysis, cross-correlation and generalized correlation motions, secondary structural analysis, and community network analysis, the conformational dynamics of the P-loop in the different states were revealed, in which the P-loop flipped into the ADP-binding site upon the inhibitor binding and interacted with the inhibitor and the C-lobe, strengthened the communication between the N- and C-lobes. These resulting interactions contributed to inhibitor selectivity profile to the STK17B. Our results may advance our understanding of kinase inhibitor selectivity and offer possible implications for the design of highly selective inhibitors for other protein kinases.

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“…The edges between node

and node

were further weighed by the corresponding

coefficients as follows:

to indicate the relative distance between nodes

during information transfer in the connection network. The obtained weighed dynamical network was used as a basis for further ‘community’ [112] and ‘optimal path’ analysis [113] , [114] , [115] , [116] . To obtain the community substructure, the Girvan-Newman divisive algorithm was applied, in which ‘edge betweenness’ that defines the number of shortest pathways across a given edge serves as an important partition criterion.…”

Section: Methodsmentioning

confidence: 99%

Atomic-scale insights into allosteric inhibition and evolutional rescue mechanism of Streptococcus thermophilus Cas9 by the anti-CRISPR protein AcrIIA6

Wang

Peng

et al. 2021

Computational and Structural Biotechnology Journal

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Protein conformational switch discerned via network centrality properties

Abstract: Graphical abstract

Cited by 30 publications

References 59 publications

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Atomic-scale insights into allosteric inhibition and evolutional rescue mechanism of Streptococcus thermophilus Cas9 by the anti-CRISPR protein AcrIIA6

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