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TitleMolecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 4630, Year 2023
Publish dateAug 2, 2023
AuthorsArthur Neuberger / Yury A Trofimov / Maria V Yelshanskaya / Jeffrey Khau / Kirill D Nadezhdin / Lena S Khosrof / Nikolay A Krylov / Roman G Efremov / Alexander I Sobolevsky /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:37532722 / PubMed Central
MethodsEM (single particle)
Resolution2.79 Å
Structure data

40676

8sp8

EMDB-40676, PDB-8sp8:
Human TRP channel TRPV6 in cNW30 nanodiscs inhibited by tetrahydrocannabivarin (THCV)
Method: EM (single particle) / Resolution: 2.79 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

ChemComp-I8E:
Tetrahydrocannabivarin

ChemComp-CA:
Unknown entry

ChemComp-CL:
Unknown entry / Chloride

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / phyto-cannabinoid / phytocannabinoid / cannabindoid / tetrahydrocannabivarin / THCV / transient receptor potential V family member 6 / TRP / human / channel / closed / TRPV6 / TRP channels / cancer / oncochannel / cNW30 / nanodiscs / circularized nanodiscs / nanodisc / vanilloid

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