Structural Basis of the Diversity of Adrenergic Receptors

• Published in: Cell reports (Cambridge) Vol. 29; no. 10; pp. 2929 - 2935.e4
• Main Authors: Qu, Lu, Zhou, Qingtong, Xu, Yueming, Guo, Yu, Chen, Xiaoyu, Yao, Deqiang, Han, Gye Won, Liu, Zhi-Jie, Stevens, Raymond C., Zhong, Guisheng, Wu, Dong, Zhao, Suwen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.12.2019; Elsevier
• Subjects: biased signaling; GPCR; partial agonism; α2A adrenergic receptor; GPCR; partial agonism; biased signaling; α2A adrenergic receptor; α(2A) adrenergic receptor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.10.088

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. [Display omitted] •Partial agonist and antagonist-bound α2AAR crystal structures are determined•F4127.39 is essential for α2AAR agonist binding, sterically and energetically•Full agonists but not partial agonists of α2AAR form hbonds with Y3946.55•ICL2 plays key role in Gs coupling of α2AAR for partial agonists 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.