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Cell Rep. 2019 Dec 3;29(10):2936-2943.e4. doi: 10.1016/j.celrep.2019.10.112.

Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor.

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing 100049, China.
2
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
3
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
4
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
5
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
6
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Biomodelling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, 02-093 Warsaw, Poland.
7
Amgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, China.
8
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
9
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhaosw@shanghaitech.edu.cn.
10
iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: wudong@shanghaitech.edu.cn.
11
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhongsh@shanghaitech.edu.cn.

Abstract

Adrenergic G-protein-coupled receptors (GPCRs) mediate different cellular signaling pathways in the presence of endogenous catecholamines and play important roles in both physiological and pathological conditions. Extensive studies have been carried out to investigate the structure and function of β adrenergic receptors (βARs). However, the structure of α adrenergic receptors (αARs) remains to be determined. Here, we report the structure of the human α2C adrenergic receptor (α2CAR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α2CAR-specific D206ECL2-R409ECL3-Y4056.58 network plays a role in determining α2 adrenergic subtype selectivity. Furthermore, our results show that a specific loosened helix at the top of TM4 in α2CAR is involved in receptor activation. Together, our structure of human α2CAR-RS79948 provides key insight into the mechanism underlying the α2 adrenergic receptor activation and subtype selectivity.

KEYWORDS:

GPCRs; JP1302; Raynaud's syndrome; crystal structure; subtype selectivity; α(2C) adrenergic receptor

PMID:
31801061
DOI:
10.1016/j.celrep.2019.10.112
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