26.06.2020: Publication Alert - SARS-CoV-2 encodes three putative ion channels: E, 8a, and 3a. Implications for the development of a therapeutic target?
Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs
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 3a forms large conductance cation channels and present cryo-EM structures of dimeric and tetrameric 3ain 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 all Alpha- and Beta-coronaviruses that infect bats and humans, suggesting therapeutics targeting 3a could treat a range of coronaviral diseases.