9m0d | pdb_00009m0d

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

spinqualitylabelsall models 9m0d, resolution 3.41Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9m0d is a 4 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.41Å Ligands: SEP, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C562_ECOLX Electron-transport protein of unknown function.NTR1_HUMAN Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMed 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 A) of NTSR1 in complex with both beta-arrestin1 and the BAM SBI-553. These structures revealed a unique "loop engagement" configuration of beta-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 beta-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. Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator.,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 HE, Tian C Cell Res. 2025 Apr;35(4):284-295. doi: 10.1038/s41422-025-01095-7. Epub 2025 Mar , 21. PMID:40118988 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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