Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Nat Commun. 2022 May 19;13(1):2795. doi: 10.1038/s41467-022-30537-8.
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.
皮肤疾病是常见的人类疾病，存在于所有文化中，发生在所有年龄段，影响着全球 30%至 70%的个体。TRPV3 是一种阳离子渗透性的 TRP 通道，主要表达于皮肤角质形成细胞，参与皮肤感觉，并与多种皮肤疾病有关。TRPV3 被局部麻醉剂地昔洛宁抑制，传统上用于局部应用以缓解疼痛和瘙痒。然而，地昔洛宁抑制 TRPV3 的结构基础仍然难以捉摸。在这里，我们呈现了一个 TRPV3-地昔洛宁复合物的冷冻电镜结构，揭示了抑制剂在连接通道周围膜环境与通道孔中心腔的门控中的结合。我们提出了 TRPV3 抑制的机制，其中地昔洛宁分子突出到通道孔中，为离子传导形成障碍。地昔洛宁的变构结合位点可以作为设计新的 TRPV3 靶向药物的模板。
