Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs.
Nat Struct Mol Biol
; 28(7): 573-582, 2021 07.
Article
in English
| MEDLINE | ID: covidwho-1279891
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Cryoelectron Microscopy
/
Nanostructures
/
Viroporin Proteins
/
SARS-CoV-2
Topics:
Vaccines
Limits:
Animals
/
Humans
Language:
English
Journal:
Nat Struct Mol Biol
Journal subject:
Molecular Biology
Year:
2021
Document Type:
Article
Affiliation country:
S41594-021-00619-0
Similar
MEDLINE
...
LILACS
LIS