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

Nat Struct Mol Biol. 2020 Dec;27(12):1202-1208. doi: 10.1038/s41594-020-00536-8. Epub 2020 Nov 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Antiviral Agents
  • Coronavirus Envelope Proteins
  • Lipid Bilayers
  • Phospholipids
  • envelope protein, SARS-CoV-2
  • 5-(N,N-hexamethylene)amiloride
  • Phenylalanine
  • Amiloride
  • Amantadine
  • Dimyristoylphosphatidylcholine