Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist

Salmeterol is a partial agonist for the beta(2) adrenergic receptor (beta(2)AR) and the first long-acting beta(2)AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol's safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound beta(2)AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between beta(1)AR and beta(2)AR explain the high receptor-subtype selectivity. A structural comparison with the beta(2)AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204(5.43) and Asn293(6.55). Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited beta-arrestin recruitment for salmeterol.