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Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation
Open accessAbstract
G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric pocket propagates conformational change to the receptor cytosolic region to promote binding and activation of downstream signalling effectors such as G proteins and β-arrestins. It is well known that different agonists can share the same binding pocket but evoke unique receptor conformations leading to a wide range of downstream responses (‘efficacy’). Furthermore, increasing biophysical evidence, primarily using the β2-adrenergic receptor (β2AR) as a model system, supports the existence of multiple active and inactive conformational states. However, how agonists with varying efficacy modulate these receptor states to initiate cellular responses is not well understood. Here we report stabilization of two distinct β2AR conformations using single domain camelid antibodies (nanobodies)—a previously described positive allosteric nanobody (Nb80) and a newly identified negative allosteric nanobody (Nb60). We show that Nb60 stabilizes a previously unappreciated low-affinity receptor state which corresponds to one of two inactive receptor conformations as delineated by X-ray crystallography and NMR spectroscopy. We find that the agonist isoprenaline has a 15,000-fold higher affinity for β2AR in the presence of Nb80 compared to the affinity of isoprenaline for β2AR in the presence of Nb60, highlighting the full allosteric range of a GPCR. Assessing the binding of 17 ligands of varying efficacy to the β2AR in the absence and presence of Nb60 or Nb80 reveals large ligand-specific effects that can only be explained using an allosteric model which assumes equilibrium amongst at least three receptor states. Agonists generally exert efficacy by stabilizing the active Nb80-stabilized receptor state (R80). In contrast, for a number of partial agonists, both stabilization of R80 and destabilization of the inactive, Nb60-bound state (R60) contribute to their ability to modulate receptor activation. These data demonstrate that ligands can initiate a wide range of cellular responses by differentially stabilizing multiple receptor states.
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“The absence of the L chain means that the nanobody’s CDRs are distinct from those of antibodies in both sequence and structure, and as a result nanobodies are able to bind antibody-inaccessible epitopes in enzyme active sites, viral capsids and G protein coupled receptors [233, 234].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [233]
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Self-citation
Metadata
- Authors
- Staus, D. P., Strachan, R. T., Manglik, A., Pani, B., Kahsai, A. W., Kim, T. H., Wingler, L. M., Ahn, S., Chatterjee, A., Masoudi, A., Kruse, A. C., Pardon, E., Steyaert, J., Weis, W. I., Prosser, R. S., Kobilka, B. K., Costa, T., & Lefkowitz, R. J.
- Affiliations
- Duke Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- Stanford Medicine (US)
- University of Toronto (CA)
- Harvard University (US)
- Vrije Universiteit Brussel (BE)
- Istituto Superiore di Sanità (IT)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kobilka, Brian K.
- Costa, Tommaso
- Lefkowitz, Robert J.
- ORCID
- Venue
- Nature
- Published
- 2016-07
- Volume
- 535
- Issue
- 7612
- Pages
- 448-452
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4961583
- OpenAlex
- W2471992026
- Cited by
- 330
- References
- 38
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 23 · 2023: 28 · 2022: 26 · 2021: 46 · 2020: 36 · 2019: 47 · 2018: 43 · 2017: 39 · 2016: 13
- FWCI
- 25.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association
- Ministero della Salute (02351158, RF-201102351158)
- National Heart, Lung, and Blood Institute (HL 16037, R01HL070631, HL-70631, T32HL007101, R01HL016037)
- National Institute of General Medical Sciences (T32GM008294)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007731)
- National Institute of Neurological Disorders and Stroke (NS-028471, R01NS028471, R37NS028471)
- 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 Structure and Dynamics
- Keywords
- beta2-adrenergic receptor, G protein-coupled receptor activation, receptor conformational states, three-state model, partial agonists, full agonists, ligand efficacy, receptor stabilization, orthosteric binding pocket, receptor dynamics
- MeSH terms
- Allosteric Regulation, Allosteric Site, Humans, Isoproterenol, Ligands, Models, Molecular, Protein Conformation, Receptors, Adrenergic, beta-2, Crystallography, X-Ray, Nuclear Magnetic Resonance, Biomolecular, Drug Partial Agonism, Protein Stability, Adrenergic beta-2 Receptor Agonists, Single-Domain Antibodies
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