8SP8

Human TRP channel TRPV6 in cNW30 nanodiscs inhibited by tetrahydrocannabivarin (THCV)

8SP8 の概要

• エントリーDOI: 10.2210/pdb8sp8/pdb
• EMDBエントリー: 40676
• 分子名称: Transient receptor potential cation channel subfamily V member 6, CHOLESTEROL HEMISUCCINATE, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate, ... (6 entities in total)
• 機能のキーワード: phyto-cannabinoid, phytocannabinoid, cannabindoid, tetrahydrocannabivarin, thcv, transient receptor potential v family member 6, trp, human, channel, closed, trpv6, trp channels, cancer, oncochannel, membrane protein, cnw30, nanodiscs, circularized nanodiscs, nanodisc, vanilloid
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 335710.45

構造登録者

Neuberger, A.,Yelshanskaya, M.V.,Nadezhdin, K.D.,Sobolevsky, A.I. (登録日: 2023-05-02, 公開日: 2023-08-23)

主引用文献

Neuberger, A.,Trofimov, Y.A.,Yelshanskaya, M.V.,Khau, J.,Nadezhdin, K.D.,Khosrof, L.S.,Krylov, N.A.,Efremov, R.G.,Sobolevsky, A.I.
Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin.
Nat Commun, 14:4630-4630, 2023

PubMed 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.

PubMed: 37532722
DOI: 10.1038/s41467-023-40362-2

実験手法

ELECTRON MICROSCOPY (2.79 Å)