人类激酶TRPV6被植物大麻素四氢大麻酚抑制的分子途径和结构机制。
Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin.
发表日期：2023 Aug 02
作者：
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
来源：
ARTHRITIS RESEARCH & THERAPY
摘要：
钙选择性癌症通道TRPV6是人类癌症中细胞增殖的重要驱动因子。尽管在药理研究中对开发TRPV6的合成抑制剂日益兴趣，但天然化合物在该通道上的作用却被大部分忽视了。另一方面，通过进化优化的天然小分子拮抗剂的药代动力学赋予了这些化合物作为强效且安全的下一代抗癌药物的药理潜力。在此，我们报道了人类TRPV6与四氢大麻酚（THCV）的复合物的结构，THCV是从大麻中提取的天然大麻素抑制剂。我们使用冷冻电镜学结合电生理学、钙成像、突变、和分子动力学模拟来识别THCV在连接膜与蛋白质中心空腔的门户中的结合位点，并表征TRPV6抑制的异源机制。我们还提出了THCV到达其结合位点的分子路径。我们的研究为新的TRPV6靶向药物的开发奠定了基础。© 2023. 作者。
The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.© 2023. The Author(s).