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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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“For example, studies have reported that PIP2 regulates the relocalization, orientation, and activity of GRK2 at the plasma membrane (71 – 74), and positively coordinates the interactions between certain GPCRs and β -arrestin (75).”
BackgroundDifferential Regulation of GPCRs—Are GRK Expression Levels the Key?
Matthees, E. S. F., Haider, R. S., Hoffmann, C., & Drube, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.687489 · Cited by 58
Mechanisms of differential desensitization of metabotropic glutamate receptors
Abreu, N., Acosta-Ruiz, A., Xiang, G., & Levitz, J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109050 · Cited by 57
“We first asked whether β-arr interacts with the G protein binding site of the TMD core of mGluR3, because such an interaction has been shown for GPCRs (Huang et al., 2020; Staus et al., 2020; Hilger et al., 2018).”
BackgroundShpakov, A. O. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076187 · Cited by 57
Negative allosteric modulation of the glucagon receptor by RAMP2
Kumar, K. K., O’Brien, E. S., Habrian, C. H., Latorraca, N. R., Wang, H., Tuneew, I., Montabana, E. A., Marqusee, S., Hilger, D., Isacoff, E. Y., et al. (2023) · Cell · doi:10.1016/j.cell.2023.02.028 · Cited by 57
Self-citationMelatonin receptor structure and signaling
Okamoto, H. H., Cecon, E., Nureki, O., Rivara, S., & Jockers, R. (2024) · Journal of Pineal Research · doi:10.1111/jpi.12952 · Cited by 56
“Recently some cryo ‐ EM structures of the GPCR – ß ‐ arrestin complex were re-ported, 33,34 but there is no structural information available of ß ‐ arrestin binding to MTRs for the moment.”
BackgroundStructural basis of GPCR coupling to distinct signal transducers: implications for biased signaling
Seyedabadi, M., Gharghabi, M., Gurevich, E. V., & Gurevich, V. V. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2022.03.009 · Cited by 57
Emerging structural insights into GPCR–β-arrestin interaction and functional outcomes
Maharana, J., Banerjee, R., Yadav, M. K., Sarma, P., & Shukla, A. K. (2022) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2022.102406 · Cited by 53
Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor
Kleist, A. B., Jenjak, S. E., Sente, A., Laskowski, L. J., Szpakowska, M., Calkins, M. M., Anderson, E. I., McNally, L. M., Heukers, R., Bobkov, V., et al. (2022) · Science · doi:10.1126/science.abj4922 · Cited by 52
Aydin, Y., Böttke, T., Lam, J. H., Ernicke, S., Anna, F., Tretbar, M., Zarzycka, B. A., Gurevich, V. V., Katritch, V., & Coin, I. (2023) · Nature Communications · doi:10.1038/s41467-023-36797-2 · Cited by 54
“In live HEK293T, we measured BRET signals upon PTH(1-34)–induced recruitment of arr2 N-terminally fused to Venus(45,46).”
BackgroundMethodInfluentialA key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes
Isaikina, P., Petrovic, I. M., Jakob, R. P., Sarma, P., Ranjan, A. K., Baruah, M., Panwalkar, V., Maier, T., Shukla, A. K., & Grzesiek, S. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.05.002 · Cited by 49
G Protein–Coupled Receptor Signaling: New Insights Define Cellular Nanodomains
Lohse, M. J., Böck, A., & Zaccolo, M. (2023) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-040623-115054 · Cited by 55
Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade
Qu, C., Park, J. Y., Yun, M. W., He, Q., Yang, F., Kim, K., Ham, D., Li, R.-R., Iverson, T. M., Gurevich, V. V., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2026491118 · Cited by 50
Key aspects of modern GPCR drug discovery
Addis, P., Bali, U., Baron, F., Campbell, A. P., Harborne, S. P. D., Jagger, L., Milne, G., Pearce, M. J., Rosethorne, E. M., Satchell, R., et al. (2023) · SLAS DISCOVERY · doi:10.1016/j.slasd.2023.08.007 · Cited by 49
“For this reason, most Cryo-EM structures of GPCRs are of the GPCR:G protein complexes and a growing number of GPCR:arrestin structures [113], as these complexes present larger particles than the receptors alone.”
BackgroundJørgensen, A. S., Daugvilaite, V., Filippo, K. D., Berg, C., Mavri, M., Benned‐Jensen, T., Juzenaite, G., Hjortø, G. M., Rankin, S. M., Våbenø, J., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02070-9 · Cited by 43
Exploring GPCR‐arrestin interfaces with genetically encoded crosslinkers
Böttke, T., Ernicke, S., Serfling, R., Ihling, C. H., Burda, E., Gurevich, V. V., Sinz, A., & Coin, I. (2020) · EMBO Reports · doi:10.15252/embr.202050437 · Cited by 45
“…et al , 2017), and the three very recent cryo-electron microscopy (cryo-EM) structures of b arr1 in complex with the class B NTS 1 R (Yin et al , 2019; Huang et al , 2020), the muscarinic acetylcholine-2-receptor (M 2 R) (Staus et al , 2020), and the b 1 -adrenoceptor ( b 1 -AR) (Lee et al , 2020).”
Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors
Maharana, J., Sano, F. K., Sarma, P., Yadav, M. K., Duan, L., Stępniewski, T. M., Chaturvedi, M., Ranjan, A. K., Singh, V., Saha, S., et al. (2024) · Science · doi:10.1126/science.adj3347 · Cited by 41
Lipid nanoparticle technologies for the study of G protein-coupled receptors in lipid environments
Lavington, S., & Watts, A. G. (2020) · Biophysical Reviews · doi:10.1007/s12551-020-00775-5 · Cited by 41
“Such an approach was successful for a recent cryo-EM structure of the NTSR1-βarrestin1 complex (Huang et al. 2020), which did not require 1297 Biophys Rev (2020) 12:1287–1302”
BackgroundMethodInfluentialStructural insights into the activation and inhibition of CXC chemokine receptor 3
Jiao, H., Pang, B., Liu, A., Chen, Q., Pan, Q., Wang, X., Xu, Y., Chiang, Y., Ren, R., & Hu, H. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01175-5 · Cited by 40
Hoppe, N., Harrison, S., Hwang, S., Chen, Z.-W., Karelina, M., Deshpande, I., Suomivuori, C., Palicharla, V. R., Berry, S. P., Tschaikner, P., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01223-8 · Cited by 42
“Indeed, the V129E 3.54 mutation maps to regions of the intracellular GPCR cavity that recent structures have demonstrated are important for engaging GPCR kinases 46,47 and β-arrestin 48,49 .”
InfluentialThe importance of the membrane for biophysical measurements
Chorev, D. S., & Robinson, C. V. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0574-1 · Cited by 42
Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism
Duan, J., He, X., Li, S., & Xu, H. E. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-024-00957-1 · Cited by 45
Beneath the surface: endosomal GPCR signaling
Flores-Espinoza, E., & Thomsen, A. R. B. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.03.006 · Cited by 46
Bon, C. L., Michon, B., Popot, J., & Zoonens, M. A. (2021) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583521000044 · Cited by 47
Renard, K., & Byrne, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169026 · Cited by 41
“Structure of the NTSR + -arrestin complex (PDB: 6UP7 [46]).”
BackgroundInfluentialBiphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR
Shiraishi, Y., Kofuku, Y., Ueda, T., Pandey, S., Dwivedi‐Agnihotri, H., Shukla, A. K., & Shimada, I. (2021) · Nature Communications · doi:10.1038/s41467-021-27482-3 · Cited by 39
Label-free visual proteomics: Coupling MS- and EM-based approaches in structural biology
Klykov, O. V., Kopylov, M., Carragher, B. O., Heck, A. J. R., Noble, A. J., & Scheltema, R. A. (2022) · Molecular Cell · doi:10.1016/j.molcel.2021.12.027 · Cited by 37
Molecular mechanism of GPCR spatial organization at the plasma membrane
Kockelkoren, G., Lauritsen, L., Shuttle, C. G., Kazepidou, E., Vonkova, I., Zhang, Y., Breuer, A., Kennard, C., Brunetti, R. M., D’Este, E., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01385-4 · Cited by 38
“…membrane proteins, H-Ras, Piezo1 and EGFR; however, we anticipate that this mechanism will affect the spatial organization of many other membrane-associated proteins, including GPCR signaling partners like G proteins and arrestins, which are hypothesized to sense membrane curvature 12,48,49 .”
Prediction of GPCR activity using machine learning
Yadav, P., Mollaei, P., Cao, Z., Wang, Y., & Farimani, A. B. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.05.016 · Cited by 38
Ivashov, V. A., Zimmer, J., Schwabl, S., Kahlhofer, J., Weys, S., Gstir, R., Jakschitz, T. A. E., Kremser, L., Bonn, G. K., Lindner, H., et al. (2020) · eLife · doi:10.7554/elife.58246 · Cited by 37
Liu, Q., He, Q., Lyu, X., Yang, F., Zhu, Z., Xiao, P., Yang, Z., Zhang, F., Yang, Z.-Y., Wang, X., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18433-5 · Cited by 37
Capturing Peptide–GPCR Interactions and Their Dynamics
Kaiser, A., & Coin, I. (2020) · Molecules · doi:10.3390/molecules25204724 · Cited by 37
Constitutive signal bias mediated by the human GHRHR splice variant 1
Cong, Z., Zhou, F., Zhang, C., Zou, X., Zhang, H., Wang, Y., Zhou, Q., Cai, X., Liu, Q., Li, J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2106606118 · Cited by 37
GPCR-dependent and -independent arrestin signaling
Gurevich, V. V., & Gurevich, E. V. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.05.007 · Cited by 36
Therapeutic approaches targeting the neurotensin receptors
Iyer, M. R., & Kunos, G. (2021) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2021.1866539 · Cited by 37
Atypical structural snapshots of human cytomegalovirus GPCR interactions with host G proteins
Tsutsumi, N., Maeda, S., Qu, Q., Vögele, M., Jude, K. M., Suomivuori, C., Panova, O., Waghray, D., KATO, H. E., Velasco, A., et al. (2022) · Science Advances · doi:10.1126/sciadv.abl5442 · Cited by 37
“6A) allows the CX3CL1-US28-Gi complex to flexibly adapt to a wide range of intermediate membrane curvatures such as these of endosomal vesicles ( 21 , 22 ).”
Self-citationProspect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine
Zhao, J., Fu, H., Yu, J., Hong, W., Tian, X., Qi, J., Sun, S., Zhao, C. S., Wu, C., Xu, Z., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36673-z · Cited by 35
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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