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Structural Mechanism Underlying TRPV1 Activation by Pungent Compounds in Gingers.

Abstract

BACKGROUND AND PURPOSE

Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive TRPV1 ion channel. How these compounds interact with TRPV1 remains unclear.

EXPERIMENTAL APPROACH

We used computational structural modeling, functional tests (electrophysiology and calcium imaging) and mutagenesis to investigate the structural mechanism for ligand-channel interactions.

KEY RESULTS

We found that the potency of three principle ginger pungent compounds-shogaol, gingerol, and zingerone-depends on the same two TRPV1 residues that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modeling revealed similar binding poses of these ginger compounds as capsaicin, including a "head-down tail-up" orientation, two specific hydrogen bonds as well as 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.

CONCLUSION AND IMPLICATIONS

Mechanistic insights on ginger compound-TRPV1 interactions should help guide pharmaceutic efforts to regulate nociception.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.

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    Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.

    ,

    Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, 95616, 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, 310058, China.

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    Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, 95616, USA.

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    Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.

    Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, 95616, USA.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31207668

    Citation

    Yin, Yue, et al. "Structural Mechanism Underlying TRPV1 Activation By Pungent Compounds in Gingers." British Journal of Pharmacology, 2019.
    Yin Y, Dong Y, Vu S, et al. Structural Mechanism Underlying TRPV1 Activation by Pungent Compounds in Gingers. Br J Pharmacol. 2019.
    Yin, Y., Dong, Y., Vu, S., Yang, F., Yarov-Yarovoy, V., Tian, Y., & Zheng, J. (2019). Structural Mechanism Underlying TRPV1 Activation by Pungent Compounds in Gingers. British Journal of Pharmacology, doi:10.1111/bph.14766.
    Yin Y, et al. Structural Mechanism Underlying TRPV1 Activation By Pungent Compounds in Gingers. Br J Pharmacol. 2019 Jun 17; PubMed PMID: 31207668.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Structural Mechanism Underlying TRPV1 Activation 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 - 2019/06/17/ PY - 2019/04/24/received PY - 2019/05/21/revised PY - 2019/05/29/accepted PY - 2019/6/18/entrez PY - 2019/6/18/pubmed PY - 2019/6/18/medline KW - capsaicin KW - gingerol KW - nociception KW - shogaol KW - spiciness KW - zingerone JF - British journal of pharmacology JO - Br. J. Pharmacol. N2 - BACKGROUND AND PURPOSE: Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive TRPV1 ion channel. How these compounds interact with TRPV1 remains unclear. EXPERIMENTAL APPROACH: We used computational structural modeling, functional tests (electrophysiology and calcium imaging) and mutagenesis to investigate the structural mechanism for ligand-channel interactions. KEY RESULTS: We found that the potency of three principle ginger pungent compounds-shogaol, gingerol, and zingerone-depends on the same two TRPV1 residues that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modeling revealed similar binding poses of these ginger compounds as capsaicin, including a "head-down tail-up" orientation, two specific hydrogen bonds as well as 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. CONCLUSION AND IMPLICATIONS: Mechanistic insights on ginger compound-TRPV1 interactions should help guide pharmaceutic efforts to regulate 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 -