8JPF

Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes

Summary for 8JPF

• Entry DOI: 10.2210/pdb8jpf/pdb
• EMDB information: 36478
• Descriptor: NTS, Neurotensin receptor type 1, 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]quinazolin-6-yl}(methyl)amino]ethan-1-ol (3 entities in total)
• Functional Keywords: biased signaling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 47577.15

Authors

Duan, J.,Liu, H.,Zhao, F.,Yuan, Q.,Ji, Y.,Xu, H.E. (deposition date: 2023-06-11, release date: 2023-08-09, Last modification date: 2023-08-30)

Primary citation

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, M.W.,Cheng, X.,Yin, W.,Jiang, Y.,Yang, D.,Xu, H.E.
GPCR activation and GRK2 assembly by a biased intracellular agonist.
Nature, 620:676-681, 2023

PubMed 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 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.

PubMed: 37532940
DOI: 10.1038/s41586-023-06395-9

Experimental method

ELECTRON MICROSCOPY (3.02 Å)