Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole

Neuberger, Arthur; Nadezhdin, Kirill D.; Sobolevsky, Alexander I.

doi:10.1038/s41467-021-26608-x

Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole

Journal Article · Mon Nov 01 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-26608-x· OSTI ID:1903932

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Columbia University, New York, NY (United States); OSTI
Columbia University, New York, NY (United States)

TRPV6 is a calcium-selective ion channel implicated in epithelial Ca²⁺ 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.

View Accepted Manuscript (DOE)

Research Organization:: Columbia University, New York, NY (United States)

Sponsoring Organization:: German Research Foundation (DFG); National Cancer Institute; National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1903932

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole

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