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Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers.
Br J Pharmacol 2019; 176(17):3364-3377BJ

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.

Authors+Show Affiliations

Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, USA.Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, USA.Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31207668

Citation

Yin, Yue, et al. "Structural Mechanisms Underlying Activation of TRPV1 Channels By Pungent Compounds in Gingers." British Journal of Pharmacology, vol. 176, no. 17, 2019, pp. 3364-3377.
Yin Y, Dong Y, Vu S, et al. Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers. Br J Pharmacol. 2019;176(17):3364-3377.
Yin, Y., Dong, Y., Vu, S., Yang, F., Yarov-Yarovoy, V., Tian, Y., & Zheng, J. (2019). Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers. British Journal of Pharmacology, 176(17), pp. 3364-3377. doi:10.1111/bph.14766.
Yin Y, et al. Structural Mechanisms Underlying Activation of TRPV1 Channels By Pungent Compounds in Gingers. Br J Pharmacol. 2019;176(17):3364-3377. PubMed PMID: 31207668.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers. AU - Yin,Yue, AU - Dong,Yawen, AU - Vu,Simon, AU - Yang,Fan, AU - Yarov-Yarovoy,Vladimir, AU - Tian,Yuhua, AU - Zheng,Jie, Y1 - 2019/07/22/ PY - 2019/04/24/received PY - 2019/05/21/revised PY - 2019/05/29/accepted PY - 2020/09/01/pmc-release PY - 2019/6/18/pubmed PY - 2019/6/18/medline PY - 2019/6/18/entrez SP - 3364 EP - 3377 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 176 IS - 17 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/31207668/Structural_Mechanism_Underlying_TRPV1_Activation_by_Pungent_Compounds_in_Gingers L2 - https://doi.org/10.1111/bph.14766 DB - PRIME DP - Unbound Medicine ER -