Structural Basis of the Diversity of Adrenergic Receptors

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.