State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
Nature. 2023 Aug;620(7974):676-681. doi: 10.1038/s41586-023-06395-9. Epub 2023 Aug 2.
Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gα and the arrestin-biased ligand SBI-553. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gα protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.
G 蛋白偶联受体（GPCRs）的磷酸化由 G 蛋白偶联受体激酶（GRKs）介导，可使 G 蛋白信号失敏，并促进衔接蛋白信号转导，而这一过程也受到偏倚配体的调节。由于 GPCR-GRK 相互作用较弱，GRK 在 GPCR 上的分子组装和 GRK 介导的偏倚信号转导的基础在很大程度上仍是未知的。在这里，我们报道了与 GRK2、Gα 和偏向配体 SBI-553 结合的神经降压素受体 1（NTSR1）的复合物结构。密度图显示了完整的 GRK2 与受体的排列方式，GRK2 的 N 端螺旋与受体的跨膜螺旋 6 的向外运动形成的开放细胞质口袋对接，类似于 G 蛋白与受体的结合。SBI-553 结合在 GRK2 和 NTSR1 之间的界面上，以增强 GRK2 的结合。SBI-553 的结合模式与衔接蛋白的结合兼容，但与 Gα 蛋白的结合相冲突，从而为其偏向衔接蛋白的信号转导能力提供了一种机制。总之，我们的结构为理解 GPCR-GRK 相互作用和 GRK2 介导的偏倚信号转导的细节提供了一个合理的模型。
