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Structural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine

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  • Arthur Neuberger

    (Columbia University)

  • Kirill D. Nadezhdin

    (Columbia University)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

Skin diseases are common human illnesses that occur in all cultures, at all ages, and affect between 30% and 70% of individuals globally. TRPV3 is a cation-permeable TRP channel predominantly expressed in skin keratinocytes, implicated in cutaneous sensation and associated with numerous skin diseases. TRPV3 is inhibited by the local anesthetic dyclonine, traditionally used for topical applications to relieve pain and itch. However, the structural basis of TRPV3 inhibition by dyclonine has remained elusive. Here we present a cryo-EM structure of a TRPV3-dyclonine complex that reveals binding of the inhibitor in the portals which connect the membrane environment surrounding the channel to the central cavity of the channel pore. We propose a mechanism of TRPV3 inhibition in which dyclonine molecules stick out into the channel pore, creating a barrier for ion conductance. The allosteric binding site of dyclonine can serve as a template for the design of new TRPV3-targeting drugs.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30537-8
    DOI: 10.1038/s41467-022-30537-8
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    1. G. D. Smith & M. J. Gunthorpe & R. E. Kelsell & P. D. Hayes & P. Reilly & P. Facer & J. E. Wright & J. C. Jerman & J.-P. Walhin & L. Ooi & J. Egerton & K. J. Charles & D. Smart & A. D. Randall & P. An, 2002. "TRPV3 is a temperature-sensitive vanilloid receptor-like protein," Nature, Nature, vol. 418(6894), pages 186-190, July.
    2. Haoxing Xu & I. Scott Ramsey & Suhas A. Kotecha & Magdalene M. Moran & Jayhong A. Chong & Deborah Lawson & Pei Ge & Jeremiah Lilly & Inmaculada Silos-Santiago & Yu Xie & Peter S. DiStefano & Rory Curt, 2002. "TRPV3 is a calcium-permeable temperature-sensitive cation channel," Nature, Nature, vol. 418(6894), pages 181-186, July.
    3. Takashi Miyamoto & Matt J. Petrus & Adrienne E. Dubin & Ardem Patapoutian, 2011. "TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin," Nature Communications, Nature, vol. 2(1), pages 1-12, September.
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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    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.

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