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Human TRPV1 structure and inhibition by the analgesic SB-366791

Author

Listed:
  • Arthur Neuberger

    (Columbia University)

  • Mai Oda

    (Yale University School of Medicine)

  • Yury A. Nikolaev

    (Yale University School of Medicine)

  • Kirill D. Nadezhdin

    (Columbia University)

  • Elena O. Gracheva

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Sviatoslav N. Bagriantsev

    (Yale University School of Medicine)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38162-9
    DOI: 10.1038/s41467-023-38162-9
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    References listed on IDEAS

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    1. Yuan Gao & Erhu Cao & David Julius & Yifan Cheng, 2016. "TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action," Nature, Nature, vol. 534(7607), pages 347-351, June.
    2. Michael J. Caterina & Mark A. Schumacher & Makoto Tominaga & Tobias A. Rosen & Jon D. Levine & David Julius, 1997. "The capsaicin receptor: a heat-activated ion channel in the pain pathway," Nature, Nature, vol. 389(6653), pages 816-824, October.
    3. Do Hoon Kwon & Feng Zhang & Justin G. Fedor & Yang Suo & Seok-Yong Lee, 2022. "Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.
    5. Maofu Liao & Erhu Cao & David Julius & Yifan Cheng, 2013. "Structure of the TRPV1 ion channel determined by electron cryo-microscopy," Nature, Nature, vol. 504(7478), pages 107-112, December.
    6. Michael J. Caterina & Tobias A. Rosen & Makoto Tominaga & Anthony J. Brake & David Julius, 1999. "A capsaicin-receptor homologue with a high threshold for noxious heat," Nature, Nature, vol. 398(6726), pages 436-441, April.
    7. 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.
    8. 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.
    9. Erhu Cao & Maofu Liao & Yifan Cheng & David Julius, 2013. "TRPV1 structures in distinct conformations reveal activation mechanisms," Nature, Nature, vol. 504(7478), pages 113-118, December.
    10. Sara L. Morales-Lázaro & Itzel Llorente & Félix Sierra-Ramírez & Ana E. López-Romero & Miguel Ortíz-Rentería & Barbara Serrano-Flores & Sidney A. Simon & León D. Islas & Tamara Rosenbaum, 2016. "Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    11. Kirill D. Nadezhdin & Arthur Neuberger & Yury A. Nikolaev & Lyle A. Murphy & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2021. "Extracellular cap domain is an essential component of the TRPV1 gating mechanism," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    12. 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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    1. Junping Fan & Han Ke & Jing Lei & Jin Wang & Makoto Tominaga & Xiaoguang Lei, 2024. "Structural basis of TRPV1 inhibition by SAF312 and cholesterol," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    2. 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.

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