Hangzhou Institute of Innovative Medicine, Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
Nat Commun. 2022 Feb 7;13(1):714. doi: 10.1038/s41467-022-28399-1.
The type 2 bradykinin receptor (B2R) is a G protein-coupled receptor (GPCR) in the cardiovascular system, and the dysfunction of B2R leads to inflammation, hereditary angioedema, and pain. Bradykinin and kallidin are both endogenous peptide agonists of B2R, acting as vasodilators to protect the cardiovascular system. Here we determine two cryo-electron microscopy (cryo-EM) structures of human B2R-G in complex with bradykinin and kallidin at 3.0 Å and 2.9 Å resolution, respectively. The ligand-binding pocket accommodates S-shaped peptides, with aspartic acids and glutamates as an anion trap. The phenylalanines at the tail of the peptides induce significant conformational changes in the toggle switch W283, the conserved PIF, DRY, and NPxxY motifs, for the B2R activation. This further induces the extensive interactions of the intracellular loops ICL2/3 and helix 8 with G proteins. Our structures elucidate the molecular mechanisms for the ligand binding, receptor activation, and G proteins coupling of B2R.
2 型缓激肽受体（B2R）是心血管系统中的 G 蛋白偶联受体（GPCR），B2R 的功能障碍导致炎症、遗传性血管性水肿和疼痛。缓激肽和赖氨酰缓激肽都是 B2R 的内源性肽激动剂，作为血管扩张剂来保护心血管系统。在这里，我们确定了人 B2R-G 与缓激肽和赖氨酰缓激肽复合物的两个冷冻电镜（cryo-EM）结构，分辨率分别为 3.0Å 和 2.9Å。配体结合口袋容纳 S 形肽，天冬氨酸和谷氨酸作为阴离子陷阱。肽尾部的苯丙氨酸诱导 toggle switch W283、保守的 PIF、DRY 和 NPxxY 基序发生显著构象变化，从而激活 B2R。这进一步诱导细胞内环 ICL2/3 和 8 螺旋与 G 蛋白的广泛相互作用。我们的结构阐明了 B2R 的配体结合、受体激活和 G 蛋白偶联的分子机制。
