9M0D

Cryo-EM structure of neurotensin receptor 1 in complex with beta-arrestin 1

This is a non-PDB format compatible entry.

Summary for 9M0D

• Entry DOI: 10.2210/pdb9m0d/pdb
• Related: 8zyt 8zyu 8zyy
• EMDB information: 63543
• Descriptor: Soluble cytochrome b562,Neurotensin receptor type 1, Beta-arrestin-1, Fab30 heavy chain, ... (4 entities in total)
• Functional Keywords: gpcr, neurotensin receptore 1, complex, beta-arrestin 1, phosphorylation, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 4
• Total formula weight: 160471.92

Authors

Sun, D.M.,Li, X.,Yuan, Q.N.,Tian, C.L. (deposition date: 2025-02-24, release date: 2025-04-09, Last modification date: 2025-04-16)

Primary citation

Sun, D.,Li, X.,Yuan, Q.,Wang, Y.,Shi, P.,Zhang, H.,Wang, T.,Sun, W.,Ling, S.,Liu, Y.,Lai, J.,Xie, W.,Yin, W.,Liu, L.,Xu, H.E.,Tian, C.
Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator.
Cell Res., 35:284-295, 2025

PubMed Abstract: Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront of drug discovery owing to their potential to selectively stimulate therapeutically relevant signaling and avoid on-target side effects. Although structures of GPCRs in complex with G protein or GRK in a BAM-bound state have recently been resolved, revealing that BAM can induce biased signaling by directly modulating interactions between GPCRs and these two transducers, no BAM-bound GPCR-arrestin complex structure has yet been determined, limiting our understanding of the full pharmacological profile of BAMs. Herein, we developed a chemical protein synthesis strategy to generate neurotensin receptor 1 (NTSR1) with defined hexa-phosphorylation at its C-terminus and resolved high-resolution cryo-EM structures (2.65-2.88 Å) of NTSR1 in complex with both β-arrestin1 and the BAM SBI-553. These structures revealed a unique "loop engagement" configuration of β-arrestin1 coupling to NTSR1 in the presence of SBI-553, markedly different from the typical "core engagement" configuration observed in the absence of BAMs. This configuration is characterized by the engagement of the intracellular loop 3 of NTSR1 with a cavity in the central crest of β-arrestin1, representing a previously unobserved, arrestin-selective conformation of GPCR. Our findings fill the critical knowledge gap regarding the regulation of GPCR-arrestin interactions and biased signaling by BAMs, which would advance the development of safer and more efficacious GPCR-targeted therapeutics.

PubMed: 40118988
DOI: 10.1038/s41422-025-01095-7

Experimental method

ELECTRON MICROSCOPY (3.41 Å)