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Structure of the neurotensin receptor 1 in complex with β-arrestin 1
Open accessAbstract
Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways 1,2. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with βarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions.
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“The structure of the phosphorylated human neurotensin receptor 1 with arrestin reveals a PI(4,5)P2 molecule forming a bridge between the receptor and arrestin [120,121].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [121]
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“The neurotensin [16,32] and vasopressin V2 [20] receptors used for determination of the structure of their complexes with arrestin-2 were the closest to the corresponding WT receptors.”
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Strategic advances for cryo-EM structural studies of small (<100 kDa) GPCRs
Singh, S. K., Agrawal, M., Pattanayak, A., Baidya, M., & Kumari, P. (2026) · Communications Biology · doi:10.1038/s42003-026-09516-y · Cited by 6
Kim, K., Ji, J. S., Kim, H. R., Choi, Y., Lee, H. H., Inoue, A., & Chung, K. Y. (2025) · Communications Biology · doi:10.1038/s42003-025-08649-w · Cited by 5
“3a, sticks), which are reported as binding sites for phosphatidylinositol 4,5-bisphosphate (PIP 2 ) 24,26,62 – 64 .”
Self-citationRamirez, M. L. G., Orduña-Castillo, L. B., Bardeleben, C., Qin, H., Lin, Y., Birch, C. A., Kufareva, I., & Trejo, J. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117041 · Cited by 4
“36 Thrombin-and APC-activated PAR1s were found to engage with β arr2 using different modes.”
Strauss, A., Gonzalez-Hernandez, A. J., Lee, J., Abreu, N., Selvakumar, P., Salas-Estrada, L. A., Kristt, M., Marx, D. C., Gilliland, K. M., Melancon, B. J., et al. (2024) · Biophysical Journal · doi:10.1016/j.bpj.2023.11.2905 · Cited by 4
Revealing the graded activation mechanism of neurotensin receptor 1
Wu, Z., Sun, X., Su, J., Zhang, X., Hu, J., & Li, C. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.134488 · Cited by 4
Nepal, B., Barnett, J., Bearoff, F. M., & Kortagere, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910470 · Cited by 4
The Role of Individual Residues in the N-Terminus of Arrestin-1 in Rhodopsin Binding
Vishnivetskiy, S. A., Paul, T., Gurevich, E. V., & Gurevich, V. V. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020715 · Cited by 4
Sarma, P., Marková, V., Dalal, A., Mishra, S., Zaidi, N., Tiwari, D., Yadav, M. K., Roy, N., Mahajan, G., Miclea, P. S., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2507384122 · Cited by 3
Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
Ngamlertwong, N., Tsuchiya, H., Mochimaru, Y., Azuma, M., Kuchimaru, T., & Koshimizu, T. (2021) · Scientific Reports · doi:10.1038/s41598-021-94894-y · Cited by 3
Agamennone, M., Nicoli, A., Bayer, S., Weber, V., Borro, L., Gupta, S. K., Fantacuzzi, M., & Pizio, A. D. (2021) · Methods in cell biology · doi:10.1016/bs.mcb.2021.06.012 · Cited by 4
Sarkar, A., Mitra, A., & Borics, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044232 · Cited by 4
“Such an interaction was also indicated in the cryo-EM structure of the active β1-adrenergic receptor (β1AR)–β-arrestin-1 complex, but it was missing from the neurotensin-1 receptor (NTS1R) bound by β-arrestin-1 [35,36].”
BackgroundMechanisms of Arrestin‐Mediated Signaling
Gurevich, V. V., & Gurevich, E. V. (2023) · Current Protocols · doi:10.1002/cpz1.821 · Cited by 4
miRNA regulation of G protein-coupled receptor mediated angiogenic pathways in cancer
Mandal, S., Chakrabarty, D., Bhattacharya, A., Paul, J., Haldar, S., & Pal, K. (2021) · The Nucleus · doi:10.1007/s13237-021-00365-0 · Cited by 4
Single-molecule analysis of receptor-β-arrestin interactions in living cellsPreprint
Grimes, J., Kőszegi, Z., Lanoiselée, Y., Miljuš, T., O’Brien, S. L., Stępniewski, T. M., Medel-Lacruz, B., Baidya, M., Makarova, M., Owen, D. M., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.15.516577 · Cited by 4
Xing, Y., Ao, J., Zhu, X., Chai, Z., & Lu, S. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104484 · Cited by 3
Structural Perspectives on Biased Allostery of GPCR Signaling
Zhao, C. S., Shen, S., Wu, C., Luo, R., Yan, W., & Shao, Z. (2025) · Handbook of experimental pharmacology · doi:10.1007/164_2025_767 · Cited by 3
Distinct membrane binding properties of the two non-visual arrestins
Killeen, T. D., Tepper, K. R., Miller, K. W., Aydin, Y., Zhuo, Y., Zhao, S., Conley, J. M., Tat, R. P., Klug, C. S., Marchese, A., et al. (2026) · Communications Biology · doi:10.1038/s42003-025-09428-3 · Cited by 3
“Previous studies show that the C-domain of Arr2/3 contains several membrane-anchoring elements: the PI(4,5)P 2 binding sites 16,30 , the C-loop 11 and the C-edge 11,16,20,21 (Fig.”
InfluentialSubtype-dependent arrestin engagement of the metabotropic glutamate receptors
Lin, S., Zhang, C., Wei, J., Li, S., Yu, J., Xu, J., Chen, K. X., Feng, Y., Wang, Z., Chu, X., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-72728-7 · Cited by 3
“Another striking difference between the glutamate – mGlu5 – β arr1 structure and the other known GPCR – arrestin structures exits in the C-edge of the arrestin, which was believed to be crucial for stabilizing the conformation of the GPCR – arrestin complex 9,11,12 .”
Do arrestin oligomers have specific functions?
Gurevich, V. V. (2023) · Cell Signaling · doi:10.46439/signaling.1.009 · Cited by 3
Shpakov, A. O. (2023) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093023070013 · Cited by 3
Post-translational modifications orchestrate the intrinsic signaling bias of GPR52
Zhang, B., Ge, W., Ma, M., Li, S., Yu, J., Yang, G., Wang, H., Li, J., Li, Q., Zeng, R., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01864-w · Cited by 3
Fujii, T., Murai, N., Aso, S., Takatsu, H., Shin, H., Katoh, Y., & Nakayama, K. (2025) · Journal of Cell Science · doi:10.1242/jcs.263793 · Cited by 6
Chemokine receptors – Exemplifying functional divergence in G protein-coupled receptors
Otun, O., Granier, S., Durroux, T., & Bechara, C. (2025) · Molecular Pharmacology · doi:10.1016/j.molpha.2025.100053 · Cited by 3
Mapping the interaction site for β-arrestin-2 in the prokineticin 2 receptor
Lattanzi, R., Casella, I., Fullone, M. R., Vincenzi, M., Maftei, D., & Miele, R. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111175 · Cited by 3
Matthees, E. S. F., Haider, R. S., Klement, L., Reichel, M., Blum, N. K., Weitzel, V., Trüpschuch, T., Ziegler, C., Drube, J., Schulz, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61281-4 · Cited by 3
β-arrestin–based biosensors: Tools to explore structural determinants of metabolic functions?
Matthees, E. S. F., Haider, R. S., & Hoffmann, C. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.09.006 · Cited by 3
Arresting Developments in Biased Signaling
Yoo, S. M., Bhardwaj, A., & Benovic, J. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.04.003 · Cited by 3
Song, W., Duncan, A. L., & Sansom, M. S. P. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.24.168260 · Cited by 2
Spantzel, L., Pérez, I., Heitkamp, T., Westphal, A., Reuter, S., Mrowka, R., & Börsch, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.05.527171 · Cited by 3
Structural Diversity and Dynamics of Metabotropic Glutamate Receptor/Beta-Arrestin CouplingPreprint
Marx, D. C., Huynh, K. W., Gonzalez-Hernandez, A. J., Strauss, A., Rico, C. A., Siepe, D. H., Gallo, P. N., Lee, J., Moshtaghin, S. S., Arefin, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.03.636340 · Cited by 3
Janetzko, J., Deutsch, J. C., Shi, Y., Siepe, D. H., Masureel, M., Liu, W., Viner, R., Inoue, A., Chu, S., Kobilka, B. K., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.06.658200 · Cited by 3
“Full-length human NTSR1 was modified with an N-terminal Flag tag followed by an octa-histidine tag and cloned into pFastBac1 vector.”
InfluentialSelf-citationChundi, A., Pham, U., Darbha, S., & Rajagopal, S. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00884 · Cited by 2
Metadata
- Authors
- Huang, W., Masureel, M., Qu, Q., Janetzko, J., Inoue, A., Kato, H. E., Robertson, M. J., Nguyen, K. C., Glenn, J. S., Skiniotis, G., & Kobilka, B. K.
- Affiliations
- Stanford Medicine (US)
- Tohoku University (JP)
- Stanford University (US)
- SLAC National Accelerator Laboratory (US)
- Corresponding author
- Skiniotis, Georgios
- Kobilka, Brian K.
- ORCID
- Venue
- Nature
- Published
- 2020-01-16
- Volume
- 579
- Issue
- 7798
- Pages
- 303-308
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7100716
- OpenAlex
- W3000145087
- Cited by
- 373
- References
- 58
- Citations by year
- 2026: 45 · 2025: 66 · 2024: 41 · 2023: 63 · 2022: 47 · 2021: 63 · 2020: 46
- FWCI
- 17.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5u19ai109662-05)
- Japan Society for the Promotion of Science (19H03163, 17K08264)
- National Cancer Institute (P30CA124435)
- National Institute of Allergy and Infectious Diseases (U19-AI109662)
- National Institute of Neurological Disorders and Stroke (R01NS028471)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- neurotensin receptor 1, β-arrestin1, G protein-coupled receptors, receptor phosphorylation, phosphatidylinositol 4,5-bisphosphate, receptor internalization, cryo-EM structure
- MeSH terms
- beta-Arrestin 1, Humans, Models, Molecular, Phosphorylation, Receptors, Neurotensin, Cryoelectron Microscopy, Protein Structure, Quaternary, Protein Stability
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