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

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Yang F, Xiao X, Cheng W, Yang W, Yu P, Song Z, Yarov-Yarovoy V, Zheng J

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

Nat Chem Biol. 2015 Jul;11(7):518-24. doi: 10.1038/nchembio.1835. Epub 2015 Jun 8.

PubMed ID

26053297 [ View in PubMed

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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-A 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zucapsaicin	Transient receptor potential cation channel subfamily V member 1	Protein	Humans	Yes	Agonist Activator	Details