Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers

Yue Yin, Yawen Dong, Simon Vu, Fan Yang, Vladimir Yarov-Yarovoy, Yuhua Tian, Jie Zheng

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background and Purpose: Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive transient receptor potential vanilloid 1 (TRPV1) ion channel. How these compounds interact with TRPV1 remains unclear. Experimental Approach: We used computational structural modelling, functional tests (electrophysiology and calcium imaging), and mutagenesis to investigate the structural mechanisms underlying ligand–channel interactions. Key Results: The potency of three principal pungent compounds from ginger —shogaol, gingerol, and zingerone—depends on the same two residues in the TRPV1 channel that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modelling revealed binding poses of these ginger compounds similar to those of capsaicin, including a “head-down tail-up” orientation, two specific hydrogen bonds, and important contributions of van der Waals interactions by the aliphatic tail. Our study also identified a novel horizontal binding pose of zingerone that allows it to directly interact with the channel pore when bound inside the ligand-binding pocket. These observations offer a molecular level explanation for how unique structures in the ginger compounds affect their channel activation potency. Conclusions and Implications: Mechanistic insights into the interactions of ginger compounds and the TRPV1 cation channel should help guide drug discovery efforts to modulate nociception.

Original languageEnglish (US)
Pages (from-to)3364-3377
Number of pages14
JournalBritish Journal of Pharmacology
Volume176
Issue number17
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Pharmacology

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