Structural Basis of the Diversity of Adrenergic Receptors

doi:10.1016/j.celrep.2019.10.088

. 2019 Dec 3;29(10):2929-2935.e4.

doi: 10.1016/j.celrep.2019.10.088.

Structural Basis of the Diversity of Adrenergic Receptors

Lu Qu¹, Qingtong Zhou², Yueming Xu², Yu Guo³, Xiaoyu Chen³, Deqiang Yao², Gye Won Han⁴, Zhi-Jie Liu³, Raymond C Stevens⁵, Guisheng Zhong⁶, Dong Wu⁷, Suwen Zhao⁸

Affiliations

¹ 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.
² iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
³ iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, 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; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
⁶ iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhongsh@shanghaitech.edu.cn.
⁷ iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: wudong@shanghaitech.edu.cn.
⁸ iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhaosw@shanghaitech.edu.cn.

PMID: 31801060
DOI: 10.1016/j.celrep.2019.10.088

Free article

Structural Basis of the Diversity of Adrenergic Receptors

Lu Qu et al. Cell Rep. 2019.

Free article

. 2019 Dec 3;29(10):2929-2935.e4.

doi: 10.1016/j.celrep.2019.10.088.

Authors

Lu Qu¹, Qingtong Zhou², Yueming Xu², Yu Guo³, Xiaoyu Chen³, Deqiang Yao², Gye Won Han⁴, Zhi-Jie Liu³, Raymond C Stevens⁵, Guisheng Zhong⁶, Dong Wu⁷, Suwen Zhao⁸

Affiliations

¹ 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.
² iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
³ iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, 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; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
⁶ iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhongsh@shanghaitech.edu.cn.
⁷ iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: wudong@shanghaitech.edu.cn.
⁸ iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhaosw@shanghaitech.edu.cn.

PMID: 31801060
DOI: 10.1016/j.celrep.2019.10.088

Abstract

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 α_2A adrenergic receptor (α_2AAR) in complex with a partial agonist and an antagonist. Key non-conserved residues from the ligand-binding pocket (Phe^7.39 and Tyr^6.55) to G-protein coupling region (Ile^34.51 and Lys^34.56) are discovered to play a key role in the interplay between partial agonism and biased signaling of α_2AAR, 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.

Keywords: GPCR; biased signaling; partial agonism; α(2A) adrenergic receptor.

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Structural Basis of the Diversity of Adrenergic Receptors

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Structural Basis of the Diversity of Adrenergic Receptors

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