Structural Basis of the Diversity of Adrenergic Receptors
Lu Qu,
Qingtong Zhou,
Yueming Xu,
Yu Guo,
Xiaoyu Chen,
Deqiang Yao,
Gye Won Han,
Zhi-Jie Liu,
Raymond C. Stevens,
Guisheng Zhong,
Dong Wu,
Suwen Zhao
Affiliations
Lu Qu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
Qingtong Zhou
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Yueming Xu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Yu Guo
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Xiaoyu Chen
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Deqiang Yao
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
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; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
Guisheng Zhong
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
Suwen Zhao
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Summary: Adrenergic receptors are highly homologous while at the same time display a wide diversity of ligand and G-protein binding, and understanding this diversity is key for designing selective or biased drugs for them. Here, we determine two crystal structures of the α2A adrenergic receptor (α2AAR) in complex with a partial agonist and an antagonist. Key non-conserved residues from the ligand-binding pocket (Phe7.39 and Tyr6.55) to G-protein coupling region (Ile34.51 and Lys34.56) are discovered to play a key role in the interplay between partial agonism and biased signaling of α2AAR, which provides insights into the diversity of ligand binding and G-protein coupling preference of adrenergic receptors and lays the foundation for the discovery of next-generation drugs targeting these receptors. : Crystal structures of α2A adrenergic receptor (α2AAR) reveal the molecular basis for the diversity in adrenergic receptors. Qu et al. define compelling roles for key amino acids in ligand binding, partial agonism, and biased signaling of α2AAR. Keywords: GPCR, α2A adrenergic receptor, partial agonism, biased signaling
