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Cell Res. 2019 Dec;29(12):971-983. doi: 10.1038/s41422-019-0256-2. Epub 2019 Nov 27.

A complex structure of arrestin-2 bound to a G protein-coupled receptor.

Author information

1
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
2
Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
3
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
4
University of Chinese Academy of Sciences, Beijing, 100049, China.
5
Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
6
Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India.
7
Laboratory of Receptor Structure and Signaling, HIT Center for Life Science, Harbin Institute of Technology, Harbin, 150001, China.
8
Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, 310058, China.
9
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. cong@sibcb.ac.cn.
10
Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, 49503, USA. Edward.Zhou@vai.org.
11
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xkyu@simm.ac.cn.
12
Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xkyu@simm.ac.cn.
13
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. eric.xu@simm.ac.cn.
14
Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, 49503, USA. eric.xu@simm.ac.cn.

Abstract

Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2‒NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2‒NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

PMID:
31776446
PMCID:
PMC6951264
[Available on 2020-12-01]
DOI:
10.1038/s41422-019-0256-2

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