PT  - JOURNAL ARTICLE
AU  - David M. Kern
AU  - Ben Sorum
AU  - Christopher M. Hoel
AU  - Savitha Sridharan
AU  - Jonathan P. Remis
AU  - Daniel B. Toso
AU  - Stephen G. Brohawn
TI  - Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs
AID  - 10.1101/2020.06.17.156554
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.17.156554
4099  - http://biorxiv.org/content/early/2020/06/18/2020.06.17.156554.short
4100  - http://biorxiv.org/content/early/2020/06/18/2020.06.17.156554.full
AB  - SARS-CoV-2 encodes three putative ion channels: E, 8a, and 3a. In related SARS-CoV-1, 3a is implicated in viral release, inflammasome activation, and cell death and its deletion reduces viral titer and morbidity in animal models, suggesting 3a-targeted therapeutics could treat SARS and COVID-19. However, the structural basis for the function of 3a is unknown. Here, we show that SARS-CoV-2 forms large conductance cation channels and present cryo-EM structures of dimeric and tetrameric SARS-CoV-2 3a in lipid nanodiscs. 3a adopts a novel fold and is captured in a closed or inactivated state. A narrow bifurcated exterior pore precludes conduction and leads to a large polar cavity open to the cytosol. 3a function is conserved in a common variant among circulating SARS-CoV-2 that alters the channel pore. We identify 3a-like proteins in Alpha- and Beta-coronaviruses that infect bats and humans, suggesting therapeutics targeting 3a could treat a range of coronaviral diseases.Competing Interest StatementThe authors have declared no competing interest.