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


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.

SUBMITTER: Yang F 

PROVIDER: S-EPMC4472570 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Yang Fan F   Xiao Xian X   Cheng Wei W   Yang Wei W   Yu Peilin P   Song Zhenzhen Z   Yarov-Yarovoy Vladimir V   Zheng Jie J  

Nature chemical biology 20150608 7


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 systema  ...[more]

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