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.
Highlights
There are nine human adrenergic receptors (a1A, a1B, a1D, a2A, a2B, a2C, b1, b2, and b3) that mediate the central and peripheral actions of catecholamines (Hein and Kobilka, 1995; Philipp and Hein, 2004a)
Numerous compounds targeting adrenergic receptors, such as b-blockers, b2 agonists, and a2 agonists, have proven to be of therapeutic benefit in the treatment of a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, and depression (MacMillan et al, 1996; Philipp and Hein, 2004a; Ruffolo et al, 1993). a2A Adrenergic receptor (a2AAR) agonists have been used for decades in clinic for the treatment of hypertension, attention-deficit/hyperactivity disorder, and anxiety because they have sympatholytic, sedating, and analgesic effects (Ruffolo et al, 1993; Tan et al, 2002)
The selectivity of a2AR is being investigated in an accompanying paper (Chen et al, 2019), we focus on understanding the structural basis of the binding and functional diversity of adrenergic receptors
Summary
There are nine human adrenergic receptors (a1A, a1B, a1D, a2A, a2B, a2C, b1, b2, and b3) that mediate the central and peripheral actions of catecholamines (Hein and Kobilka, 1995; Philipp and Hein, 2004a). A2A Adrenergic receptor (a2AAR) agonists have been used for decades in clinic for the treatment of hypertension, attention-deficit/hyperactivity disorder, and anxiety because they have sympatholytic, sedating, and analgesic effects (Ruffolo et al, 1993; Tan et al, 2002). Adrenergic receptors couple to different G proteins, with a1, a2, and b types mainly coupling to Gq, Gi/o, and Gs, respectively (Lefkowitz et al, 1988). A2AAR mainly couples to Gi, whereas at high concentrations, Gs coupling dominates. This unusual dual effect has not been well explained for any G-protein-coupled receptor (GPCR)
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