Structural Basis of the Diversity of Adrenergic Receptors

作者：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 · 发表于：Cell Reports · 年份：2019 · DOI：10.1016/j.celrep.2019.10.088 · 被引用次数：49 · 研究领域：Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology、Pharmacological Effects and Assays

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 2A AR) 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 2A AR, 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.