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Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

Author

Listed:
  • Arthur Neuberger

    (Columbia University)

  • Yury A. Trofimov

    (Russian Academy of Sciences)

  • Maria V. Yelshanskaya

    (Columbia University)

  • Jeffrey Khau

    (Columbia University)

  • Kirill D. Nadezhdin

    (Columbia University)

  • Lena S. Khosrof

    (Columbia University)

  • Nikolay A. Krylov

    (Russian Academy of Sciences)

  • Roman G. Efremov

    (Russian Academy of Sciences)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.

Suggested Citation

  • Arthur Neuberger & Yury A. Trofimov & Maria V. Yelshanskaya & Jeffrey Khau & Kirill D. Nadezhdin & Lena S. Khosrof & Nikolay A. Krylov & Roman G. Efremov & Alexander I. Sobolevsky, 2023. "Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40362-2
    DOI: 10.1038/s41467-023-40362-2
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    References listed on IDEAS

    as
    1. Luke L. McGoldrick & Appu K. Singh & Kei Saotome & Maria V. Yelshanskaya & Edward C. Twomey & Robert A. Grassucci & Alexander I. Sobolevsky, 2018. "Opening of the human epithelial calcium channel TRPV6," Nature, Nature, vol. 553(7687), pages 233-237, January.
    2. Appu K. Singh & Kei Saotome & Luke L. McGoldrick & Alexander I. Sobolevsky, 2018. "Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    3. Ruth A. Pumroy & Anna D. Protopopova & Tabea C. Fricke & Iris U. Lange & Ferdinand M. Haug & Phuong T. Nguyen & Pamela N. Gallo & Bárbara B. Sousa & Gonçalo J. L. Bernardes & Vladimir Yarov-Yarovoy & , 2022. "Structural insights into TRPV2 activation by small molecules," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Arthur Neuberger & Mai Oda & Yury A. Nikolaev & Kirill D. Nadezhdin & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2023. "Human TRPV1 structure and inhibition by the analgesic SB-366791," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    5. Stephen B. Long & Xiao Tao & Ernest B. Campbell & Roderick MacKinnon, 2007. "Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment," Nature, Nature, vol. 450(7168), pages 376-382, November.
    6. Arthur Neuberger & Yury A. Trofimov & Maria V. Yelshanskaya & Kirill D. Nadezhdin & Nikolay A. Krylov & Roman G. Efremov & Alexander I. Sobolevsky, 2023. "Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2022. "Structural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    8. Kei Saotome & Appu K. Singh & Maria V. Yelshanskaya & Alexander I. Sobolevsky, 2016. "Crystal structure of the epithelial calcium channel TRPV6," Nature, Nature, vol. 534(7608), pages 506-511, June.
    9. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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