Format

Send to

Choose Destination
Cell Rep. 2019 Dec 3;29(10):2929-2935.e4. doi: 10.1016/j.celrep.2019.10.088.

Structural Basis of the Diversity of Adrenergic Receptors.

Author information

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.

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 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.

KEYWORDS:

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

PMID:
31801060
DOI:
10.1016/j.celrep.2019.10.088
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center