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

  • Author(s): Yang, Fan
  • Xiao, Xian
  • Cheng, Wei
  • Yang, Wei
  • Yu, Peilin
  • Song, Zhenzhen
  • Yarov-Yarovoy, Vladimir
  • Zheng, Jie
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472570/
No data is associated with this publication.
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.

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