Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist. (November 2018)

• Record Type: Journal Article
• Authors: Masureel, Matthieu; Zou, Yaozhong; Picard, Louis-Philippe; Westhuizen, Emma; Mahoney, Jacob; Rodrigues, João; Mildorf, Thomas; Dror, Ron; Shaw, David; Bouvier, Michel; Pardon, Els; Steyaert, Jan; Sunahara, Roger; Weis, William; Zhang, Cheng; Kobilka, Brian
• Is Part Of: Nature chemical biology. Volume 14:Number 11(2018)
• Page Start: 1059
• Page End: 1066
• Publication Date: 2018-11
• Subjects: Biochemistry -- Periodicals; Biochimie -- Périodiques; 572.05
• DOI: 10.1038/s41589-018-0145-x
• Languages: English
• ISSNs: 1552-4450

Abstract

Abstract Salmeterol is a partial agonist for the β2 adrenergic receptor (β2 AR) and the first long-acting β2 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 β2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β1 AR and β2 AR explain the high receptor-subtype selectivity. A structural comparison with the β2 AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser2045.43 and Asn2936.55 . 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 β-arrestin recruitment for salmeterol. The active-state structure of a GPCR occupied by a partial agonist, β2 AR with salmeterol, together with mutagenesis and biophysical studies, explains this ligand's unusual pharmacological profile.