3a Ion channel

Tags: target

Description:

RCSB: 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.

RCSB PDB: 6XDC 6XDC

Related interactions

Target	Drug	Type	Result
3a Ion channel	Capreomycin	In vitro	positive
3a Ion channel	Pentamidine	In vitro	positive
3a Ion channel	Spectinomycin	In vitro	positive
3a Ion channel	Kasugamycin	In vitro	positive
3a Ion channel	Plerixafor	In vitro	positive
3a Ion channel	Flumatinib	In vitro	positive
3a Ion channel	Litronesib	Computational	positive
3a Ion channel	Darapladib	In vitro	positive
3a Ion channel	Floxuridine	In vitro	positive
3a Ion channel	Fludarabine	In vitro	positive

Related publications

Title	Author	Type
Blockers of the SARS-CoV-2 3a Channel Identified by Targeted Drug Repurposing	Prabhat Pratap Singh Tomar, Miriam Krugliak, Isaiah T. Arkin	Research