EMD-36475

Single-particle
3.07 Å
EMD-36475 Deposition: 11/06/2023
Map released: 09/08/2023
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-36475

cryo-EM structure of NTSR1-GRK2-Galpha(q) complexes 2

EMD-36475

Single-particle
3.07 Å
EMD-36475 Deposition: 11/06/2023
Map released: 09/08/2023
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, synthetic construct, Bos taurus
Sample: NTSR1-GRK2-Galpha(q) complexes 2
Fitted models: 8jpc (Avg. Q-score: 0.458)

Deposition Authors: Duan J , Liu H, Zhao F, Yuan Q, Ji Y, Xu HE
GPCR activation and GRK2 assembly by a biased intracellular agonist.
Duan J , Liu H, Zhao F, Yuan Q, Ji Y, Cai X, He X , Li X, Li J, Wu K, Gao T, Zhu S, Lin S, Wang MW , Cheng X , Yin W , Jiang Y, Yang D , Xu HE
(2023) Nature , 620 , 676 - 681
PUBMED: 37532940
DOI: doi:10.1038/s41586-023-06395-9
ISSN: 1476-4687
ASTM: NATUAS
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.