Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist
Open accessAbstract
Salmeterol is a partial agonist for the β 2 adrenergic receptor (β 2 AR) and the first long-acting β 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 β 2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β 1 AR and β 2 AR explain the high receptor-subtype selectivity. A structural comparison with the β 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 β-arrestin recruitment for salmeterol.
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ADRs possess a flexible agonist pocket.
“Because ADRs possess a flexible agonist pocket (Masureel et al., 2018)”
From A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors (2020) · cites this paper as Masureel et al., 2018
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- Authors
- Masureel, M., Zou, Y., Picard, L.-P., van der Westhuizen, E., Mahoney, J. P., Rodrigues, J. P. G. L. M., Mildorf, T. J., Dror, R. O., Shaw, D. E., Bouvier, M., Pardon, E., Steyaert, J., Sunahara, R. K., Weis, W. I., Zhang, C., & Kobilka, B. K.
- Affiliations
- Stanford Medicine (US)
- Institute for Research in Immunology and Cancer (CA)
- University of Michigan (US)
- D. E. Shaw Research (US)
- Vrije Universiteit Brussel (BE)
- University of California San Diego (US)
- University of Pittsburgh (US)
- Corresponding author
- Zhang, Cheng
- Kobilka, Brian K.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2018-10-16
- Volume
- 14
- Issue
- 11
- Pages
- 1059-1066
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6197491
- OpenAlex
- W2897059447
- Cited by
- 194
- References
- 61
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 18 · 2023: 19 · 2022: 29 · 2021: 32 · 2020: 32 · 2019: 25 · 2018: 1
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-11-30)
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- Monash University Research Portal (Monash University) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- American Heart Association (17POST33410958, 13PRE17110027)
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007767, R01GM083118, U19GM106990, R35GM122543, R35GM128641)
- National Institute of Neurological Disorders and Stroke (R01NS028471)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- salmeterol, beta2-adrenergic receptor, partial agonists, GPCR crystal structures, nanobodies, receptor subtype selectivity, exosite, hydrogen bond network, G protein activation, β-arrestin recruitment, long-acting beta2-agonists, asthma, chronic obstructive pulmonary disease
- MeSH terms
- Salmeterol Xinafoate, beta-Arrestins, Animals, Antibodies, Asthma, Binding Sites, Computer Simulation, Humans, Hydrogen Bonding, Ligands, Lipids, Protein Binding, Protein Conformation, Signal Transduction, Mutagenesis, Receptors, Adrenergic, beta-2, Crystallography, X-Ray, GTP-Binding Proteins, Pulmonary Disease, Chronic Obstructive, Adrenergic beta-2 Receptor Agonists
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