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

Xiaoyu Chen; Yueming Xu; Lu Qu; Lijie Wu; Gye Won Han; Yu Guo; Yiran Wu; Qingtong Zhou; Qianqian Sun; Cenfeng Chu; Jie Yang; Liu Yang; Quan Wang; Shuguang Yuan; Ling Wang; Tao Hu; Houchao Tao; Yaping Sun; Yunpeng Song; Liaoyuan Hu; Zhi-Jie Liu; Raymond C Stevens; Suwen Zhao; Dong Wu; Guisheng Zhong

doi:10.1016/j.celrep.2019.10.112

Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α_2C Adrenergic Receptor

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

Authors

Xiaoyu Chen¹, Yueming Xu², Lu Qu³, Lijie Wu², Gye Won Han⁴, Yu Guo⁵, Yiran Wu², Qingtong Zhou², Qianqian Sun², Cenfeng Chu⁵, Jie Yang⁵, Liu Yang⁵, Quan Wang⁵, Shuguang Yuan⁶, Ling Wang², Tao Hu¹, Houchao Tao², Yaping Sun⁷, Yunpeng Song⁷, Liaoyuan Hu⁷, Zhi-Jie Liu⁸, Raymond C Stevens⁸, Suwen Zhao⁹, Dong Wu¹⁰, Guisheng Zhong¹¹

Affiliations

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.

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

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 α_2C adrenergic receptor (α_2CAR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α_2CAR-specific D206^ECL2-R409^ECL3-Y405^6.58 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 α_2CAR is involved in receptor activation. Together, our structure of human α_2CAR-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CHO Cells
Cell Line
Cricetulus
HEK293 Cells
Humans
Isoquinolines / pharmacology
Ligands
Naphthyridines / pharmacology
Receptors, Adrenergic, alpha-2 / metabolism*
Receptors, G-Protein-Coupled / metabolism
Signal Transduction / drug effects

Substances

Isoquinolines
Ligands
Naphthyridines
RS 79948-197
Receptors, Adrenergic, alpha-2
Receptors, G-Protein-Coupled