tetano
Editor, Senior Moderator
Nat Struct Mol Biol
. 2021 Jun 22.
doi: 10.1038/s41594-021-00619-0. Online ahead of print.
Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs
David M Kern[SUP] 1 2 3 [/SUP], Ben Sorum[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Sonali S Mali[SUP] #[/SUP][SUP] 1 2 [/SUP], Christopher M Hoel[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Savitha Sridharan[SUP] 1 2 [/SUP], Jonathan P Remis[SUP] 3 [/SUP], Daniel B Toso[SUP] 3 [/SUP], Abhay Kotecha[SUP] 4 [/SUP], Diana M Bautista[SUP] 5 6 [/SUP], Stephen G Brohawn[SUP] 7 8 9 [/SUP]
Affiliations
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[SUP]2+[/SUP]-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.
. 2021 Jun 22.
doi: 10.1038/s41594-021-00619-0. Online ahead of print.
Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs
David M Kern[SUP] 1 2 3 [/SUP], Ben Sorum[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Sonali S Mali[SUP] #[/SUP][SUP] 1 2 [/SUP], Christopher M Hoel[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Savitha Sridharan[SUP] 1 2 [/SUP], Jonathan P Remis[SUP] 3 [/SUP], Daniel B Toso[SUP] 3 [/SUP], Abhay Kotecha[SUP] 4 [/SUP], Diana M Bautista[SUP] 5 6 [/SUP], Stephen G Brohawn[SUP] 7 8 9 [/SUP]
Affiliations
- PMID: 34158638
- DOI: 10.1038/s41594-021-00619-0
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[SUP]2+[/SUP]-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.