Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein.
Structure
; 30(8): 1062-1074.e4, 2022 08 04.
Article
em En
| MEDLINE
| ID: mdl-35660160
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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Glicoproteína da Espícula de Coronavírus
/
SARS-CoV-2
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article