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1.
Structure ; 30(8): 1062-1074.e4, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35660160

RESUMO

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.


Assuntos
SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Benzeno , Microscopia Crioeletrônica , Simulação de Dinâmica Molecular , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
2.
Elife ; 102021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33554856

RESUMO

The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped the S:ACE2 interaction interface and uncovered long-range allosteric propagation of ACE2 binding to sites necessary for host-mediated proteolysis of S protein, critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat [HR]) regions ~130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the prefusion state. Our findings provide a dynamics map of the S:ACE2 interface in solution and also offer mechanistic insights into how ACE2 binding is allosterically coupled to distal proteolytic processing sites and viral-host membrane fusion. Thus, protease docking sites flanking the S1/S2 cleavage site represent alternate allosteric hotspot targets for potential therapeutic development.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Sítio Alostérico , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Sítios de Ligação , COVID-19/metabolismo , Humanos , Espectrometria de Massas/métodos , Simulação de Dinâmica Molecular , Ligação Proteica , Processamento de Proteína Pós-Traducional , Proteólise , Receptores Virais/química , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus
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