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Nat Chem Biol. 2015 Jul;11(7):518-524. doi: 10.1038/nchembio.1835. Epub 2015 Jun 8.

Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.

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Department of Physiology and Membrane Biology, University of California, Davis, California 95616, United States.
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Department of Toxicology, School of Public health, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, China.
Contributed equally


Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Although a capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2- to 4.5-Å resolution, capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions--important details required for mechanistic understanding. We obtained the missing atomic-level details by iterative computation and confirmed them by systematic site-specific functional tests. We observed that the bound capsaicin takes a 'tail-up, head-down' configuration. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes TRPV1's open state by 'pull-and-contact' interactions between the vanillyl group and the S4-S5 linker. Our study provides a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrates an effective approach to obtain atomic-level information from cryo-EM structures.

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