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Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole
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Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole
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Journal Article
Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole
2021
Overview
TRPV6 is a calcium-selective ion channel implicated in epithelial Ca
2+
uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, including cancers. Here we combine cryo-EM, calcium imaging, and mutagenesis to explore molecular bases of human TRPV6 inhibition by the antifungal drug econazole and the universal ion channel blocker ruthenium red (RR). Econazole binds to an allosteric site at the channel’s periphery, where it replaces a lipid. In contrast, RR inhibits TRPV6 by binding in the middle of the ion channel’s selectivity filter and plugging its pore like a bottle cork. Despite different binding site locations, both inhibitors induce similar conformational changes in the channel resulting in closure of the gate formed by S6 helices bundle crossing. The uncovered molecular mechanisms of TRPV6 inhibition can guide the design of a new generation of clinically useful inhibitors.
TRPV6 is a calcium-selective ion channel that is involved in numerous calcium-dependent physiological processes and it is of interest as a potential drug target. Here, the authors present the cryo-EM structures of human TRPV6 with the bound inhibitors ruthenium red and the antifungal drug econazole and discuss their inhibition mechanisms.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/28
/ 14/35
/ 14/63
/ 82/16
/ 82/29
/ 82/80
/ 82/83
/ Antifungal Agents - chemistry
/ Calcium
/ Calcium Channel Blockers - chemistry
/ Calcium Channels - chemistry
/ Calcium Channels - metabolism
/ Helices
/ Humanities and Social Sciences
/ Humans
/ Lipids
/ Science
/ TRPV Cation Channels - antagonists & inhibitors
/ TRPV Cation Channels - chemistry
