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other·preclinical research, biomedical research, ophthalmology, oncology, research methods·PMC10397291

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

Nature Communications · 9 authors, 2 centres

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TL;DR

This study used cryo-electron microscopy and molecular dynamics simulations to reveal how tetrahydrocannabivarin (THCV) inhibits the human TRPV6 calcium channel. The research found that THCV binds to a specific side portal site, stabilizing the channel in a closed state.

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The study employed cryo-electron microscopy to determine the structure of the human TRPV6 channel in complex with the phytocannabinoid tetrahydrocannabivarin (THCV) and used molecular dynamics simulations to model its pathway. The central result was that THCV inhibits TRPV6 by binding to a deep portal site connecting the channel pore to the membrane, distinct from previously characterized ligand sites. This binding stabilizes a closed-state conformation through a unique allosteric mechanism. The implications are that this structural insight could guide the development of THCV-inspired inhibitors for diseases involving TRPV6 dysregulation, such as cancer.

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other

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preclinical research

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ORIGINAL PAPER

PMC10397291

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

Nature Communications

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ABSTRACT

Abstract 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 from Cannabis 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. Subject terms: Transient receptor potential channels, Cryoelectron microscopy

CITATION EXPORT

Arthur Neuberger, Yury A Trofimov, Maria V Yelshanskaya et al.. Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin. Nature Communications. (2023). https://doi.org/10.1038/s41467-023-40362-2

AUTHORS

9 · 2 CENTRES

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

1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY USA
2Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia