Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
Graduate School of Medicine, Mie University, 2-174 Edobashi Tsu, Mie, 514-8507, Japan.
Commun Biol. 2024 Oct 16;7(1):1303. doi: 10.1038/s42003-024-06905-z.
Endothelin type B receptor (ETR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETR activation by the endogenous peptide hormones endothelin (ET)-1-3 stimulates several signaling pathways, including G, G, G, G, and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ETR possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ETR-G complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ETR activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ETR and organizing the assembly of the binding pocket for the α5 helix of G protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies.
内皮素 B 型受体 (ETR) 在调节血压和体液平衡中发挥着关键作用，使其成为相关疾病的重要治疗靶点。内源性肽激素内皮素 (ET)-1-3 激活 ETR 可刺激包括 G、G、G、G 和β-arrestin 在内的多种信号通路。尽管跨膜螺旋 7 (TM7) 中的保守 NPxxY 基序在 GPCR 激活过程中很重要，但 ETR 还具有不太为人知的 NPxxL 基序。在这项研究中，我们呈现了 ETR-G 复合物的冷冻电镜结构，并结合 MD 模拟和功能研究进行了补充。这些研究揭示了 ETR 激活过程中 TM7 向细胞内侧的异常运动，以及多样化 NPxxL 基序在稳定 ETR 活性构象和组织 G 蛋白 α5 螺旋结合口袋组装方面的重要作用。这些发现增进了我们对 GPCR 和 G 蛋白之间相互作用的理解，从而推动了治疗策略的发展。
