6T4G

ROR(gamma)t ligand binding domain in complex with cholesterol and allosteric ligand FM26

Summary for 6T4G

• Entry DOI: 10.2210/pdb6t4g/pdb
• Descriptor: Nuclear receptor ROR-gamma, CHOLESTEROL, 4-[(~{E})-[3-[2-chloranyl-6-(trifluoromethyl)phenyl]-5-(1~{H}-pyrrol-3-yl)-1,2-oxazol-4-yl]methylideneamino]benzoic acid, ... (5 entities in total)
• Functional Keywords: nuclear receptor, allosteric, inverse agonist, inhibitor, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31452.72

Authors

de Vries, R.M.J.M.,Meijer, F.A.,Brunsveld, L. (deposition date: 2019-10-14, release date: 2020-11-25, Last modification date: 2024-01-24)

Primary citation

de Vries, R.M.J.M.,Meijer, F.A.,Doveston, R.G.,Leijten-van de Gevel, I.A.,Brunsveld, L.
Cooperativity between the orthosteric and allosteric ligand binding sites of ROR gamma t.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

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 RORγt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORγt 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 RORγt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.

PubMed: 33536342
DOI: 10.1073/pnas.2021287118

Experimental method

X-RAY DIFFRACTION (1.93 Å)