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

Fan Yang, Xian Xiao, Wei Cheng, Wei Yang, Peilin Yu, Zhenzhen Song, Vladimir Yarov-Yarovoy, Jie Zheng

Research output: Contribution to journalArticle

110 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)518-524
Number of pages7
JournalNature Chemical Biology
Volume11
Issue number7
DOIs
StatePublished - Jul 20 2015

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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