Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt
Open accessAbstract
Significance: RORγt is a nuclear receptor associated with several diseases. Various synthetic ligands have been developed that target the canonical orthosteric or a second, allosteric pocket of RORγt. We show that orthosteric and allosteric ligands can simultaneously bind to RORγt and that their potency is positively influenced by the other ligand, a phenomenon called cooperative dual ligand binding. The mechanism behind cooperative binding in proteins is poorly understood, primarily due to the lack of structural data. We solved 12 crystal structures of RORγt, simultaneously bound to various orthosteric and allosteric ligands. In combination with molecular dynamics, we reveal a mechanism responsible for the cooperative binding behavior. Our comprehensive structural studies provide unique insights into how cooperative binding occurs in proteins.
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Allosteric drugs have higher specificity and lower toxicity due to targeting nonconserved allosteric sites.
“Due to its higher specificity and consequently lower toxicity, which results from targeting nonconserved allosteric sites, allostery also increasingly features in allosteric drugs.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [122]
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AlphaFold, Artificial Intelligence (AI), and Allostery
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- Authors
- de Vries, R. M. J. M., Meijer, F. A., Doveston, R. G., Leijten-van de Gevel, I. A., & Brunsveld, L.
- Affiliations
- Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, 5612 AZ Eindhoven, The Netherlands;
- Eindhoven University of Technology (NL)
- University of Leicester (GB)
- Corresponding author
- Brunsveld, Luc
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-02-03
- Volume
- 118
- Issue
- 6
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC8017705
- OpenAlex
- W3127226292
- Cited by
- 38
- References
- 63
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 9 · 2021: 8
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- TU/e Research Portal (publishedVersion, cc-by-nc-nd)
- Figshare (submittedVersion, cc-by-nc-nd)
- TU/e Research Portal (submittedVersion, cc-by-nc-nd)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.150.366, 024.001.035)
- EC | Horizon 2020 (H2020-MSCA-IEF-2016)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- RORγt, cooperative binding, nuclear receptors, allosteric pocket, inverse agonists, agonists, ternary complex structure, autoimmune disease
- MeSH terms
- Allosteric Regulation, Allosteric Site, Binding Sites, Humans, Ligands, Molecular Conformation, Protein Binding, Protein Conformation, Crystallography, X-Ray, Biophysical Phenomena, Drug Discovery, Molecular Dynamics Simulation, Nuclear Receptor Subfamily 1, Group F, Member 3
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