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Structural mechanism of TRPV3 channel inhibition by the plant-derived coumarin osthole

Published on 09.02.2021 in EMBO Reports

Authors:

Arthur Neuberger, Kirill D. Nadezhdin, Eleonora Zakharian, Alexander I. Sobolevsky

Coumarin osthole, an active ingredient of plant Cnidium monnieri, which is shown in this picture, is used in traditional Chinese medicine for the treatment of skin-related diseases, such as atopic dermatitis, itch, vaginitis, and vulva eczema. Neuberger et al. show that osthole produces a competitive inhibition of TRP channel TRPV3, which is predominantly expressed in skin keratinocytes and shown in this picture as a molecular surface with four subunits colored differently, by binding at two sites per subunit and converting the channel into a previously unidentified conformation.

TRPV3, a representative of the vanilloid subfamily of TRP channels, is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin pathologies and cancers. TRPV3 is inhibited by the natural coumarin derivative osthole, an active ingredient of Cnidium monnieri, which has been used in traditional Chinese medicine for the treatment of a variety of human diseases. However, the structural basis of channel inhibition by osthole has remained elusive. Here we present cryo-EM structures of TRPV3 in complex with osthole, revealing two types of osthole binding sites in the transmembrane region of TRPV3 that coincide with the binding sites of agonist 2-APB. Osthole binding converts the channel pore into a previously unidentified conformation with a widely open selectivity filter and closed intracellular gate. Our structures provide insight into competitive inhibition of TRPV3 by osthole and can serve as a template for the design of osthole chemistry-inspired drugs targeting TRPV3-associated diseases.

This work was done in collaboration with Dr. Ella Zakharian group from University of Illinois College of Medicine, Peoria, IL, USA.