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A distinct structural mechanism underlies TRPV1 activation by piperine.

Abstract

Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.

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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.

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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 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.

    ,

    Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China. Electronic address: yhtian05250@qdu.edu.cn.

    Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, 95616, USA. Electronic address: jzheng@ucdavis.edu.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31213294

    Citation

    Dong, Yawen, et al. "A Distinct Structural Mechanism Underlies TRPV1 Activation By Piperine." Biochemical and Biophysical Research Communications, vol. 516, no. 2, 2019, pp. 365-372.
    Dong Y, Yin Y, Vu S, et al. A distinct structural mechanism underlies TRPV1 activation by piperine. Biochem Biophys Res Commun. 2019;516(2):365-372.
    Dong, Y., Yin, Y., Vu, S., Yang, F., Yarov-Yarovoy, V., Tian, Y., & Zheng, J. (2019). A distinct structural mechanism underlies TRPV1 activation by piperine. Biochemical and Biophysical Research Communications, 516(2), pp. 365-372. doi:10.1016/j.bbrc.2019.06.039.
    Dong Y, et al. A Distinct Structural Mechanism Underlies TRPV1 Activation By Piperine. Biochem Biophys Res Commun. 2019 Aug 20;516(2):365-372. PubMed PMID: 31213294.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A distinct structural mechanism underlies TRPV1 activation by piperine. AU - Dong,Yawen, AU - Yin,Yue, AU - Vu,Simon, AU - Yang,Fan, AU - Yarov-Yarovoy,Vladimir, AU - Tian,Yuhua, AU - Zheng,Jie, Y1 - 2019/06/15/ PY - 2019/05/01/received PY - 2019/06/07/accepted PY - 2020/08/20/pmc-release PY - 2019/6/20/pubmed PY - 2019/6/20/medline PY - 2019/6/20/entrez KW - Agonist KW - CPZ KW - Capsaicin KW - ECS KW - Nociception KW - Pepper KW - Pungency KW - Spice KW - TRPA1 KW - The abbreviations used are KW - VDW KW - capsazepine KW - extracellular solution KW - mTRPV1 KW - mouse transient receptor potential cation channel, subfamily V, member 1 KW - transient receptor potential cation channel, subfamily A, member 1 KW - van der Waals SP - 365 EP - 372 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 516 IS - 2 N2 - Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/31213294/A_distinct_structural_mechanism_underlies_TRPV1_activation_by_piperine L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(19)31162-3 DB - PRIME DP - Unbound Medicine ER -