Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers

Venkata S Mandala; Matthew J McKay; Alexander A Shcherbakov; Aurelio J Dregni; Antonios Kolocouris; Mei Hong

doi:10.1038/s41594-020-00536-8

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Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers

Journal article

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Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers

Venkata S Mandala, Matthew J McKay, Alexander A Shcherbakov, Aurelio J Dregni, Antonios Kolocouris and Mei Hong

Nature structural & molecular biology, Vol.27(12), pp.1202-1208

12/01/2020

DOI: 10.1038/s41594-020-00536-8

PMCID: PMC7718435

PMID: 33177698

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Abstract

An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E's transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs.

Amantadine - chemistry

Amiloride - analogs & derivatives

Amiloride - chemistry

Antiviral Agents - chemistry

Coronavirus Envelope Proteins - chemistry

Coronavirus Envelope Proteins - genetics

Dimyristoylphosphatidylcholine - chemistry

Hydrogen-Ion Concentration

Lipid Bilayers - chemistry

Magnetic Resonance Spectroscopy

Models, Molecular

Phenylalanine - chemistry

Phospholipids - chemistry

Protein Conformation

Protein Domains

SARS-CoV-2 - chemistry

SARS-CoV-2 - genetics

Details

Title: Subtitle: Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers
Creators: Venkata S Mandala - Massachusetts Institute of Technology
Matthew J McKay - Massachusetts Institute of Technology
Alexander A Shcherbakov - Massachusetts Institute of Technology
Aurelio J Dregni - Massachusetts Institute of Technology
Antonios Kolocouris - National and Kapodistrian University of Athens
Mei Hong - Massachusetts Institute of Technology
Resource Type: Journal article
Publication Details: Nature structural & molecular biology, Vol.27(12), pp.1202-1208
DOI: 10.1038/s41594-020-00536-8
PMID: 33177698
PMCID: PMC7718435
NLM abbreviation: Nat Struct Mol Biol
ISSN: 1545-9993
eISSN: 1545-9985
Grant note: F31 AG069418 / NIA NIH HHS P41 GM111135 / NIGMS NIH HHS R01 GM088204 / NIGMS NIH HHS GM088204 / U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) P41 GM132079 / NIGMS NIH HHS GM132079 / U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) S10 OD023513 / NIH HHS GM111135 / U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health)
Language: English
Date published: 12/01/2020
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9985112883202771

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