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GPCR activation and GRK2 assembly by a biased intracellular agonist

Published:2 August 2023 DOI: 10.1038/s41586-023-06395-9 PMID: 37532940
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, H. Eric Xu

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. Structural studies on the complex containing G-protein-coupled receptor kinase 2 (GRK2), neurotensin receptor 1 (NTSR1), Gαq and the arrestin-biased ligand SBI-553 provide insights into these interactions and a foundation for the design of arrestin-biased ligands for G-protein-coupled receptors.

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Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
SBI-553 1849603-72-0 C26H31FN4O2 29 suppliers Inquiry
SBI-553 1849603-72-0 C26H31FN4O2 29 suppliers Inquiry
SBI-553 1849603-72-0 C26H31FN4O2 29 suppliers Inquiry
SBI-553 1849603-72-0 C26H31FN4O2 29 suppliers Inquiry

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