Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 27, Issue 12, Pages 1202-U270Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-00536-8
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Funding
- National Institutes of Health [GM088204]
- MIT School of Science Sloan Fund
- NIH [P41 GM111135, P41 GM132079]
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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-angstrom 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 alpha-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. A solid-state NMR structure of the transmembrane domain from SARS-CoV-2 envelope protein in the phospholipid environment reveals determinants of cation selectivity, a dehydrated pore and an N-terminal drug-binding site.
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