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Structural insights into TRPV2 activation by small molecules

Author

Listed:
  • Ruth A. Pumroy

    (University of Pennsylvania)

  • Anna D. Protopopova

    (University of Pennsylvania)

  • Tabea C. Fricke

    (Hannover Medical School)

  • Iris U. Lange

    (Hannover Medical School)

  • Ferdinand M. Haug

    (Hannover Medical School)

  • Phuong T. Nguyen

    (University of California)

  • Pamela N. Gallo

    (University of Pennsylvania)

  • Bárbara B. Sousa

    (Universidade de Lisboa)

  • Gonçalo J. L. Bernardes

    (Universidade de Lisboa
    University of Cambridge)

  • Vladimir Yarov-Yarovoy

    (University of California)

  • Andreas Leffler

    (Hannover Medical School)

  • Vera Y. Moiseenkova-Bell

    (University of Pennsylvania)

Abstract

Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30083-3
    DOI: 10.1038/s41467-022-30083-3
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    References listed on IDEAS

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    2. Benedikt Goretzki & Christoph Wiedemann & Brett A. McCray & Stefan L. Schäfer & Jasmin Jansen & Frederike Tebbe & Sarah-Ana Mitrovic & Julia Nöth & Ainara Claveras Cabezudo & Jack K. Donohue & Cy M. J, 2023. "Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. 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.
    5. Yandong Zhou & Michelle R. Jennette & Guolin Ma & Sarah A. Kazzaz & James H. Baraniak & Robert M. Nwokonko & Mallary L. Groff & Marcela Velasquez-Reynel & Yun Huang & Youjun Wang & Donald L. Gill, 2023. "An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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