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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.

Author information

1
Department of Physiology and Membrane Biology, University of California, Davis, California 95616, United States.
2
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
3
Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
4
Department of Toxicology, School of Public health, Zhejiang University, Hangzhou, Zhejiang 310058, China.
5
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, China.
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Contributed equally

Abstract

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.

PMID:
26053297
PMCID:
PMC4472570
DOI:
10.1038/nchembio.1835
[Indexed for MEDLINE]
Free PMC Article

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