GPCR activation and GRK2 assembly by a biased intracellular agonist

Jia Duan (), Heng Liu, Fenghui Zhao, Qingning Yuan, Yujie Ji, Xiaoqing Cai, Xinheng He, Xinzhu Li, Junrui Li, Kai Wu, Tianyu Gao, Shengnan Zhu, Shi Lin, Ming-Wei Wang, Xi Cheng, Wanchao Yin, Yi Jiang, Dehua Yang () and H. Eric Xu ()
Additional contact information
Jia Duan: Chinese Academy of Sciences
Heng Liu: Chinese Academy of Sciences
Fenghui Zhao: Chinese Academy of Sciences
Qingning Yuan: Chinese Academy of Sciences
Yujie Ji: Chinese Academy of Sciences
Xiaoqing Cai: Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Xinzhu Li: Chinese Academy of Sciences
Junrui Li: Chinese Academy of Sciences
Kai Wu: Chinese Academy of Sciences
Tianyu Gao: Chinese Academy of Sciences
Shengnan Zhu: Chinese Academy of Sciences
Shi Lin: Research Center for Deepsea Bioresources
Ming-Wei Wang: Research Center for Deepsea Bioresources
Xi Cheng: Chinese Academy of Sciences
Wanchao Yin: Chinese Academy of Sciences
Yi Jiang: Lingang Laboratory
Dehua Yang: University of Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences

Nature, 2023, vol. 620, issue 7974, 676-681

Abstract: Abstract 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 ligands1–6. 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, Gαq 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 Gαq 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.

Date: 2023
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DOI: 10.1038/s41586-023-06395-9

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