TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site

Nadezhdin, Kirill D.; Neuberger, Arthur; Khosrof, Lena S.; Talyzina, Irina A.; Khau, Jeffrey; Yelshanskaya, Maria V.; Sobolevsky, Alexander I.

doi:10.1126/sciadv.adn2453

TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site

Journal Article · Wed May 01 00:00:00 EDT 2024 · Science Advances

DOI:https://doi.org/10.1126/sciadv.adn2453· OSTI ID:2471644

^[1]; ^[1]; ^[1]; Talyzina, Irina A. ^[1]; ^[1]; ^[1]; ^[1]

Columbia Univ., New York, NY (United States)

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.

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:: 2471644

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 18 Vol. 10; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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