6XDC

Cryo-EM structure of SARS-CoV-2 ORF3a

Summary for 6XDC

• Entry DOI: 10.2210/pdb6xdc/pdb
• EMDB information: 22136 22138 22139
• Descriptor: ORF3a protein (1 entity in total)
• Functional Keywords: sars-cov-2, coronavirus, viroporin, ion channel, transport protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 64331.80

Authors

Kern, D.M.,Hoel, C.M.,Brohawn, S.G. (deposition date: 2020-06-10, release date: 2020-06-17, Last modification date: 2024-05-15)

Primary citation

Kern, D.M.,Sorum, B.,Mali, S.S.,Hoel, C.M.,Sridharan, S.,Remis, J.P.,Toso, D.B.,Kotecha, A.,Bautista, D.M.,Brohawn, S.G.
Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs.
Nat.Struct.Mol.Biol., 28:573-582, 2021

PubMed 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 Ca-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.

PubMed: 34158638
DOI: 10.1038/s41594-021-00619-0

Experimental method

ELECTRON MICROSCOPY (2.9 Å)