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Oligomeric State and Drug Binding of the SARS-CoV-2 Envelope Protein Are Sensitive to the Ectodomain.
Somberg, Noah H; Sucec, Iva; Medeiros-Silva, João; Jo, Hyunil; Beresis, Richard; Syed, Abdullah M; Doudna, Jennifer A; Hong, Mei.
Afiliación
  • Somberg NH; Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, Massachusetts 02139, United States.
  • Sucec I; Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, Massachusetts 02139, United States.
  • Medeiros-Silva J; Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, Massachusetts 02139, United States.
  • Jo H; Department of Pharmaceutical Chemistry, University of California San Francisco, 555 Mission Bay Blvd. South, San Francisco, California 94158, United States.
  • Beresis R; Department of Pharmaceutical Chemistry, University of California San Francisco, 555 Mission Bay Blvd. South, San Francisco, California 94158, United States.
  • Syed AM; Gladstone Institute of Data Science and Biotechnology, San Francisco, California 94158, United States.
  • Doudna JA; Innovative Genomics Institute, University of California Berkeley, Berkeley, California 94720, United States.
  • Hong M; Gladstone Institute of Data Science and Biotechnology, San Francisco, California 94158, United States.
J Am Chem Soc ; 146(35): 24537-24552, 2024 Sep 04.
Article en En | MEDLINE | ID: mdl-39167680
ABSTRACT
The envelope (E) protein of SARS-CoV-2 is the smallest of the three structural membrane proteins of the virus. E mediates budding of the progeny virus in the endoplasmic reticulum Golgi intermediate compartment of the cell. It also conducts ions, and this channel activity is associated with the pathogenicity of SARS-CoV-2. The structural basis for these functions is still poorly understood. Biochemical studies of E in detergent micelles found a variety of oligomeric states, but recent 19F solid-state NMR data indicated that the transmembrane domain (ETM, residues 8-38) forms pentamers in lipid bilayers. Hexamethylene amiloride (HMA), an E inhibitor, binds the pentameric ETM at the lipid-exposed helix-helix interface. Here, we investigate the oligomeric structure and drug interaction of an ectodomain-containing E construct, ENTM (residues 1-41). Unexpectedly, 19F spin diffusion NMR data reveal that ENTM adopts an average oligomeric state of dimers instead of pentamers in lipid bilayers. A new amiloride inhibitor, AV-352, shows stronger inhibitory activity than HMA in virus-like particle assays. Distance measurements between 13C-labeled protein and a trifluoromethyl group of AV-352 indicate that the drug binds ENTM with a higher stoichiometry than ETM. We measured protein-drug contacts using a sensitivity-enhanced two-dimensional 13C-19F distance NMR technique. The results indicate that AV-352 binds the C-terminal half of the TM domain, similar to the binding region of HMA. These data provide evidence for the existence of multiple oligomeric states of E in lipid bilayers, which may carry out distinct functions and may be differentially targeted by antiviral drugs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Amilorida / Proteínas de la Envoltura de Coronavirus / SARS-CoV-2 Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Amilorida / Proteínas de la Envoltura de Coronavirus / SARS-CoV-2 Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos