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Salmeterol is a partial agonist for the β2 adrenergic receptor (β2AR), and the first long-acting β2AR agonist (LABA) to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol has been controversial both for its safety and mechanism of action. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β2AR in complex with an active-state stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β1AR and β2AR explain the high receptor subtype selectivity. A structural comparison with the β2AR bound to the full agonist epinephrine reveals differences in the hydrogen bond network involving residues Ser 2045.43 and Asn 2936.55. Mutagenesis and biophysical studies suggest that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G protein activation and the limited β-arrestin recruitment for salmeterol.

In the version of this paper originally published, the structure for epinephrine shown in Figure 1a was redrawn with an extra carbon. The structure has been replaced in the HTML and PDF versions of the article. The original and corrected versions of the structure are shown below.