Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

Neuberger, Arthur; Trofimov, Yury A.; Yelshanskaya, Maria V.; Khau, Jeffrey; Nadezhdin, Kirill D.; Khosrof, Lena S.; Krylov, Nikolay A.; Efremov, Roman G.; Sobolevsky, Alexander I.

doi:10.1038/s41467-023-40362-2

Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

Journal Article · Wed Aug 02 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-40362-2· OSTI ID:2424175

^[1]; ^[2]; Yelshanskaya, Maria V. ^[1]; ^[1]; ^[1]; Khosrof, Lena S. ^[1]; ^[2]; Efremov, Roman G. ^[2]; ^[1]

Columbia Univ., New York, NY (United States)
Russian Academy of Sciences (RAS), Moscow (Russian Federation)

The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted fromCannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2424175

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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