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TitleTRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site.
Journal, issue, pagesSci Adv, Vol. 10, Issue 18, Page eadn2453, Year 2024
Publish dateMay 3, 2024
AuthorsKirill D Nadezhdin / Arthur Neuberger / Lena S Khosrof / Irina A Talyzina / Jeffrey Khau / Maria V Yelshanskaya / Alexander I Sobolevsky /
PubMed AbstractTRPV3 represents both temperature- and ligand-activated transient receptor potential (TRP) channel. Physiologically relevant opening of TRPV3 channels by heat has been captured structurally, while ...TRPV3 represents both temperature- and ligand-activated transient receptor potential (TRP) channel. Physiologically relevant opening of TRPV3 channels by heat has been captured structurally, while opening by agonists has only been observed in structures of mutant channels. Here, we present cryo-EM structures that illuminate opening and inactivation of wild-type human TRPV3 in response to binding of two types of agonists: either the natural cannabinoid tetrahydrocannabivarin (THCV) or synthetic agonist 2-aminoethoxydiphenylborane (2-APB). We found that THCV binds to the vanilloid site, while 2-APB binds to the S1-S4 base and ARD-TMD linker sites. Despite binding to distally located sites, both agonists induce similar pore opening and cause dissociation of a lipid that occupies the vanilloid site in their absence. Our results uncover different but converging allosteric pathways through which small-molecule agonists activate TRPV3 and provide a framework for drug design and understanding the role of lipids in ion channel function.
External linksSci Adv / PubMed:38691614 / PubMed Central
MethodsEM (single particle)
Resolution2.46 - 3.68 Å
Structure data

42994

8v6k

EMDB-42994, PDB-8v6k:
Apo-state cryo-EM structure of human TRPV3 in cNW30 nanodiscs
Method: EM (single particle) / Resolution: 2.46 Å

42995

8v6l

EMDB-42995, PDB-8v6l:
Open-state cryo-EM structure of human TRPV3 in presence of tetrahydrocannabivarin (THCV) in cNW30 nanodiscs
Method: EM (single particle) / Resolution: 3.68 Å

42996

8v6m

EMDB-42996, PDB-8v6m:
Inactivated-state cryo-EM structure of human TRPV3 in presence of tetrahydrocannabivarin (THCV) in cNW30 nanodiscs
Method: EM (single particle) / Resolution: 3.63 Å

42997

8v6n

EMDB-42997, PDB-8v6n:
Open-state cryo-EM structure of human TRPV3 in presence of 2-APB in cNW30 nanodiscs
Method: EM (single particle) / Resolution: 2.59 Å

42998

8v6o

EMDB-42998, PDB-8v6o:
Inactivated-state cryo-EM structure of human TRPV3 in presence of 2-APB in cNW30 nanodiscs
Method: EM (single particle) / Resolution: 2.83 Å

Chemicals

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

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-I8E:
Tetrahydrocannabivarin

ChemComp-ACD:
ARACHIDONIC ACID / Arachidonic acid

ChemComp-FZ4:
2-aminoethyl diphenylborinate / 2-Aminoethoxydiphenyl borate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / transient receptor potential V family member 3 / TRP / channel / TRPV3 / TRP channels / tetrahydrocannabivarin / THCV / 2-Aminoethoxydiphenylborane / 2-APB

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