Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs

David M. Kern, Ben Sorum, Sonali S. Mali, Christopher M. Hoel, Savitha Sridharan, Jonathan P. Remis, Daniel B. Toso, Abhay Kotecha, Diana M. Bautista, Stephen G. Brohawn

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Here, we present structures of SARS-CoV-2 3a determined by cryo-EM to 2.1-Å resolution. 3a adopts a new fold with a polar cavity that opens to the cytosol and membrane through separate water- and lipid-filled openings. Hydrophilic grooves along outer helices could form ion-conduction paths. Using electrophysiology and fluorescent ion imaging of 3a-reconstituted liposomes, we observe Ca2+-permeable, nonselective cation channel activity, identify mutations that alter ion permeability and discover polycationic inhibitors of 3a activity. 3a-like proteins are found across coronavirus lineages that infect bats and humans, suggesting that 3a-targeted approaches could treat COVID-19 and other coronavirus diseases.

Original languageEnglish (US)
Pages (from-to)573-582
Number of pages10
JournalNature Structural and Molecular Biology
Volume28
Issue number7
DOIs
StatePublished - Jul 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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