Download MendeleyCooperativity between the orthosteric and allosteric ligand binding sites of ROR gamma t.
de Vries, R.M.J.M., Meijer, F.A., Doveston, R.G., Leijten-van de Gevel, I.A., Brunsveld, L.(2021) Proc Natl Acad Sci U S A 118
- PubMed: 33536342
- DOI: https://doi.org/10.1073/pnas.2021287118
- Primary Citation of Related Structures:
6T4G, 6T4I, 6T4J, 6T4K, 6T4T, 6T4U, 6T4W, 6T4X, 6T4Y, 6T50, 6TLQ, 6TLT - PubMed Abstract:
Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for ROR¦Ăt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of ROR¦Ăt simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric ROR¦Ăt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.
Organizational Affiliation:
Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, 5612 AZ Eindhoven, The Netherlands.
