8ZYY
Cryo-EM structure of neurotensin receptor 1 in complex with beta-arrestin1 and SBI-553 (complex 2)
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Summary for 8ZYY
| Entry DOI | 10.2210/pdb8zyy/pdb |
| EMDB information | 60583 |
| Descriptor | Beta-arrestin-1, Fab30 heavy chain, neurotensin peptide 8-13, ... (7 entities in total) |
| Functional Keywords | neurotensin receptor, beta-arrestin1, phosphorylation, intracellular agonist, sbi-553, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 162502.07 |
| Authors | |
| 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 Cited by 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: 40118988DOI: 10.1038/s41422-025-01095-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.83 Å) |
Structure validation
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