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
Affiliations
Xiaoyu Chen
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
Yueming Xu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Lu Qu
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
Lijie Wu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Gye Won Han
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
Yu Guo
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
Yiran Wu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Qingtong Zhou
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Qianqian Sun
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Cenfeng Chu
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
Jie Yang
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
Liu Yang
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
Quan Wang
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
Shuguang Yuan
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
Ling Wang
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Tao Hu
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
Houchao Tao
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Yaping Sun
Amgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, China
Yunpeng Song
Amgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, China
Liaoyuan Hu
Amgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, China
Zhi-Jie Liu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Raymond C. Stevens
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Suwen Zhao
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Dong Wu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Guisheng Zhong
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Summary: 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. : Chen et al. report the crystal structure of human α2CAR and the functional experimental results, which indicate that extracellular regions determine α2 adrenergic subtype selectivity. The structural and functional results provide the molecular explanation for α2CAR selective ligands and insights to understand GPCR subtype selectivity. Keywords: α2C adrenergic receptor, subtype selectivity, crystal structure, GPCRs, Raynaud's syndrome, JP1302
