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Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein.
Zuzic, Lorena; Samsudin, Firdaus; Shivgan, Aishwary T; Raghuvamsi, Palur V; Marzinek, Jan K; Boags, Alister; Pedebos, Conrado; Tulsian, Nikhil K; Warwicker, Jim; MacAry, Paul; Crispin, Max; Khalid, Syma; Anand, Ganesh S; Bond, Peter J.
  • 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.
Structure ; 30(8): 1062-1074.e4, 2022 08 04.
Article in English | MEDLINE | ID: covidwho-1946637
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / SARS-CoV-2 Type of study: Prognostic study Topics: Vaccines / Variants Language: English Journal: Structure Journal subject: Molecular Biology / Biochemistry / Biotechnology Year: 2022 Document Type: Article Affiliation country: J.str.2022.05.006

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / SARS-CoV-2 Type of study: Prognostic study Topics: Vaccines / Variants Language: English Journal: Structure Journal subject: Molecular Biology / Biochemistry / Biotechnology Year: 2022 Document Type: Article Affiliation country: J.str.2022.05.006