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^1,2,3,4,5,6. 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_q and the arrestin-biased ligand SBI-553⁷. 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_q 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.

GPCR 激酶 (GRK) 对 G 蛋白偶联受体 (GPCR) 的磷酸化使 G 蛋白信号传导脱敏并促进抑制蛋白信号传导，该信号传导也受到偏向配体的调节^1,2,3,4,5,6 。由于 GPCR-GRK 相互作用较弱，GRK 在 GPCR 上的分子组装以及 GRK 介导的偏向信号传导的基础在很大程度上仍然未知。在这里，我们报告了与 GRK2、Gα _q和抑制蛋白偏向配体 SBI-553 ⁷结合的神经降压素受体 1 (NTSR1) 的复杂结构。密度图揭示了完整GRK2与受体的排列，GRK2的N端螺旋对接至受体跨膜螺旋6向外运动形成的开放胞质袋中，类似于G蛋白与受体的结合受体。 SBI-553 结合在 GRK2 和 NTSR1 之间的界面以增强 GRK2 结合。 SBI-553 的结合模式与抑制蛋白结合兼容，但与 Gα _q蛋白的结合发生冲突，从而为其偏向抑制蛋白的信号传导能力提供了机制。总之，我们的结构为理解 GPCR-GRK 相互作用和 GRK2 介导的偏向信号传导的细节提供了一个合理的模型。