Cited by 382Receptor Mechanisms and SignalingNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

Structure of the neurotensin receptor 1 in complex with β-arrestin 1

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Huang, Weijiao, Masureel, Matthieu, Qu, Qianhui, Janetzko, John, Inoue, Asuka, Kato, Hideaki E., Robertson, Michael J., Nguyen, Khanh C. +3 more·2020·Nature

Abstract

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.

    “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].”

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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.
Venue
Nature
Published
2020-01-16
Volume
579
Issue
7798
Pages
303-308
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3000145087
Cited by
373
References
58
Citations by year
2026: 45 · 2025: 66 · 2024: 41 · 2023: 63 · 2022: 47 · 2021: 63 · 2020: 46 · 2019: 1
FWCI
17.62
Type
journal article
Language
en
Open access
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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