Journal Article

FZJ-2023-02416

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Combining structural and coevolution information to unveil allosteric sites

La Sala, G. (Corresponding author) ; Pfleger, C. ; Käck, H. ; Wissler, L. ; Nevin, P. ; Böhm, K. ; Janet, J. P. ; Schimpl, M. ; Stubbs, C. J. ; De Vivo, M. ; Tyrchan, C. ; Hogner, A. ; Gohlke, H. (Corresponding author)FZJ* ; Frolov, A. I. (Corresponding author)

2023
RSC Cambridge

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Please use a persistent id in citations: doi:10.1039/D2SC06272K  doi:10.34734/FZJ-2023-02416

Abstract: Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets.

Note: This is an open access publication.

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Contributing Institute(s):

1. John von Neumann - Institut für Computing (NIC)
2. Jülich Supercomputing Center (JSC)
3. Strukturbiochemie (IBI-7)
4. Bioinformatik (IBG-4)

Research Program(s):

1. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
2. 2171 - Biological and environmental resources for sustainable use (POF4-217) (POF4-217)
3. Forschergruppe Gohlke (hkf7_20200501) (hkf7_20200501)

Appears in the scientific report 2023

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Database coverage:
; ; ; ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; National-Konsortium ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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