Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein.

Autor:	Zuzic L; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore; Department of Chemistry, Faculty of Science and Engineering, Manchester Institute of Biotechnology, The University of Manchester, Manchester M1 7DN, UK., Samsudin F; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore., Shivgan AT; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore., Raghuvamsi PV; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore., Marzinek JK; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore., Boags A; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore; School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK., Pedebos C; School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK., Tulsian NK; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117546, Singapore., Warwicker J; School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Institute of Biotechnology, The University of Manchester, Manchester M1 7DN, UK., MacAry P; Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore 117546, Singapore., Crispin M; School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK., Khalid S; School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. Electronic address: syma.khalid@bioch.ox.ac.uk., Anand GS; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: gsa5089@psu.edu., Bond PJ; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address: peterjb@bii.a-star.edu.sg.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2022 Aug 04; Vol. 30 (8), pp. 1062-1074.e4. Date of Electronic Publication: 2022 Jun 03.
DOI:	10.1016/j.str.2022.05.006
Abstrakt:	The COVID-19 pandemic has prompted a rapid response in vaccine and drug development. Herein, we modeled a complete membrane-embedded SARS-CoV-2 spike glycoprotein and used molecular dynamics simulations with benzene probes designed to enhance discovery of cryptic pockets. This approach recapitulated lipid and host metabolite binding sites previously characterized by cryo-electron microscopy, revealing likely ligand entry routes, and uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop. A full representation of glycan moieties was essential to accurately describe pocket dynamics. A multi-conformational behavior of the 617-628 loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry experiments, supportive of opening and closing dynamics. The pocket is the site of multiple mutations associated with increased transmissibility found in SARS-CoV-2 variants of concern including Omicron. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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