瞬时受体电位通道
变构调节
化学
TRPV公司
生物物理学
连接器
兴奋剂
结合位点
离子通道
受体
细胞生物学
TRPV1型
生物化学
生物
计算机科学
操作系统
作者
Kirill D. Nadezhdin,Arthur Neuberger,Lena S. Khosrof,Irina A. Talyzina,Jeffrey Khau,M.V. Yelshanskaya,Alexander I. Sobolevsky
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-05-03
卷期号:10 (18)
标识
DOI:10.1126/sciadv.adn2453
摘要
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.
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