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Nat Chem Biol. 2018 Nov;14(11):1059-1066. doi: 10.1038/s41589-018-0145-x. Epub 2018 Oct 16.

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

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
2
Geneus Technologies, Ltd, Chengdu, Sichuan, People's Republic of China.
3
Department of Biochemistry, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada.
4
Monash Institute for Pharmaceutical Sciences, Monash University, Victoria, Australia.
5
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
6
Department of Computer Science, Stanford University, Stanford, CA, USA.
7
Department of Structural Biology, Stanford University, Stanford, CA, USA.
8
D. E. Shaw Research, New York, NY, USA.
9
Dropbox, New York, NY, USA.
10
Department of Computer Science and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
11
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
12
Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
13
Structural Biology Research Center, VIB, Brussels, Belgium.
14
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA.
15
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. chengzh@pitt.edu.
16
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.

Abstract

Salmeterol is a partial agonist for the β2 adrenergic receptor (β2AR) and the first long-acting β2AR 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 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 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.

PMID:
30327561
PMCID:
PMC6197491
DOI:
10.1038/s41589-018-0145-x
[Indexed for MEDLINE]
Free PMC Article

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