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 alpha(2A) adrenergic receptor (alpha(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 alpha(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.