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A naturally occurring G11S mutation in the 3C-like protease from the SARS-CoV-2 virus dramatically weakens the dimer interface.
Wang, Guanyu; Venegas, Felipe A; Rueda, Andres M; Weerasinghe, Nuwani W; Uggowitzer, Kevin A; Thibodeaux, Christopher J; Moitessier, Nicolas; Mittermaier, Anthony K.
Afiliación
  • Wang G; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Venegas FA; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Rueda AM; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Weerasinghe NW; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Uggowitzer KA; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Thibodeaux CJ; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Moitessier N; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
  • Mittermaier AK; Department of Chemistry, McGill University, Montreal, Quebec, Canada.
Protein Sci ; 33(1): e4857, 2024 Jan.
Article en En | MEDLINE | ID: mdl-38058248
The 3C-like protease (3CLpro ) is crucial to the replication of SARS-CoV-2, the causative agent of COVID-19, and is the target of several successful drugs including Paxlovid and Xocova. Nevertheless, the emergence of viral resistance underlines the need for alternative drug strategies. 3CLpro only functions as a homodimer, making the protein-protein interface an attractive drug target. Dimerization is partly mediated by a conserved glycine at position 11. However, some naturally occurring SARS-CoV-2 sequences contain a serine at this position, potentially disrupting the dimer. We have used concentration-dependent activity assays and mass spectrometry to show that indeed the G11S mutation reduces the stability of the dimer by 600-fold. This helps to set a quantitative benchmark for the minimum potency required of any future protein-protein interaction inhibitors targeting 3CLpro and raises interesting questions regarding how coronaviruses bearing such weakly dimerizing 3CLpro enzymes are capable of replication.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: SARS-CoV-2 / COVID-19 Límite: Humans Idioma: En Revista: Protein Sci Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: SARS-CoV-2 / COVID-19 Límite: Humans Idioma: En Revista: Protein Sci Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos