IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30083-3.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30083-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-30083-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yuki Katanosaka & Keiichiro Iwasaki & Yoshihiro Ujihara & Satomi Takatsu & Koki Nishitsuji & Motoi Kanagawa & Atsushi Sudo & Tatsushi Toda & Kimiaki Katanosaka & Satoshi Mohri & Keiji Naruse, 2014. "TRPV2 is critical for the maintenance of cardiac structure and function in mice," Nature Communications, Nature, vol. 5(1), pages 1-14, September.
    2. Kevin W. Huynh & Matthew R. Cohen & Jiansen Jiang & Amrita Samanta & David T. Lodowski & Z. Hong Zhou & Vera Y. Moiseenkova-Bell, 2016. "Structure of the full-length TRPV2 channel by cryo-EM," Nature Communications, Nature, vol. 7(1), pages 1-8, September.
    3. 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.
    4. Lejla Zubcevic & Mark A. Herzik & Mengyu Wu & William F. Borschel & Marscha Hirschi & Albert S. Song & Gabriel C. Lander & Seok-Yong Lee, 2018. "Conformational ensemble of the human TRPV3 ion channel," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    5. 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.
    6. 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.
    7. 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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Demin Ma & Yueming Zheng & Xiaoxiao Li & Xiaoyu Zhou & Zhenni Yang & Yan Zhang & Long Wang & Wenbo Zhang & Jiajia Fang & Guohua Zhao & Panpan Hou & Fajun Nan & Wei Yang & Nannan Su & Zhaobing Gao & Ji, 2023. "Ligand activation mechanisms of human KCNQ2 channel," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. 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.
    2. 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.
    3. Barbara Storti & Carmine Di Rienzo & Francesco Cardarelli & Ranieri Bizzarri & Fabio Beltram, 2015. "Unveiling TRPV1 Spatio-Temporal Organization in Live Cell Membranes," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-17, March.
    4. 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.
    5. 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.
    6. 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.
    7. Maxim V Nikolaev & Natalia A Dorofeeva & Margarita S Komarova & Yuliya V Korolkova & Yaroslav A Andreev & Irina V Mosharova & Eugene V Grishin & Denis B Tikhonov & Sergey A Kozlov, 2017. "TRPV1 activation power can switch an action mode for its polypeptide ligands," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-16, May.
    8. 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.
    9. 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.
    10. Heng Zhang & Jia-Jia Lin & Ya-Kai Xie & Xiu-Zu Song & Jia-Yi Sun & Bei-Lei Zhang & Yun-Kun Qi & Zhen-Zhong Xu & Fan Yang, 2023. "Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    11. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    12. Kirill D. Nadezhdin & Irina A. Talyzina & Aravind Parthasarathy & Arthur Neuberger & David X. Zhang & Alexander I. Sobolevsky, 2023. "Structure of human TRPV4 in complex with GTPase RhoA," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Ringsmuth, Andrew K. & Landsberg, Michael J. & Hankamer, Ben, 2016. "Can photosynthesis enable a global transition from fossil fuels to solar fuels, to mitigate climate change and fuel-supply limitations?," Renewable and Sustainable Energy Reviews, Elsevier, vol. 62(C), pages 134-163.
    14. Michael J. Maxwell & Chris Thekkedam & Cedric Lamboley & Yanni K.-Y. Chin & Theo Crawford & Jennifer J. Smith & Junyu Liu & Xinying Jia & Irina Vetter & Derek R. Laver & Bradley S. Launikonis & Angela, 2023. "A bivalent remipede toxin promotes calcium release via ryanodine receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30083-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.