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

Weijiao Huang, Matthieu Masureel, Qianhui Qu, John Janetzko, Asuka Inoue, Hideaki E. Kato, Michael J. Robertson, Khanh C. Nguyen, Jeffrey S. Glenn, Georgios Skiniotis () and Brian K. Kobilka ()
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Weijiao Huang: Stanford University School of Medicine
Matthieu Masureel: Stanford University School of Medicine
Qianhui Qu: Stanford University School of Medicine
John Janetzko: Stanford University School of Medicine
Asuka Inoue: Tohoku University
Hideaki E. Kato: Stanford University School of Medicine
Michael J. Robertson: Stanford University School of Medicine
Khanh C. Nguyen: Stanford University
Jeffrey S. Glenn: Stanford University
Georgios Skiniotis: Stanford University School of Medicine
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2020, vol. 579, issue 7798, 303-308

Abstract: 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 pathways1,2. 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.

Date: 2020
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DOI: 10.1038/s41586-020-1953-1

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