The human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4.

中文翻译：

---

激动剂复合人TRPV4离子通道的Cryo-EM结构研究显示新颖的结构重排导致开放构象

人类瞬态受体电位香草酸4（hTRPV4）离子通道在多种生物学过程中起着至关重要的作用。虽然已经报道了hTRPV4选通特性的激活可用于广谱的刺激，包括合成的4α-佛波醇，但对激活的分子基础了解甚少。在这里，我们报告在原型佛波酸激动剂4α-PDD存在下确定的hTRPV4的新型冷冻电磁结构。互补诱变实验支持EM识别的结合位点，并允许合理化位于4α-PDD结合位点之外的破坏性突变体。这项工作代表了hTRPV4在配体诱导的开放构象中的第一个结构信息。一起，