RT Journal Article
SR Electronic
T1 Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.17.156554
DO 10.1101/2020.06.17.156554
A1 David M. Kern
A1 Ben Sorum
A1 Christopher M. Hoel
A1 Savitha Sridharan
A1 Jonathan P. Remis
A1 Daniel B. Toso
A1 Stephen G. Brohawn
YR 2020
UL http://biorxiv.org/content/early/2020/06/18/2020.06.17.156554.abstract
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.