6SAL
ROR(gamma)t ligand binding domain in complex with allosteric ligand FM26
Summary for 6SAL
| Entry DOI | 10.2210/pdb6sal/pdb |
| Descriptor | Nuclear receptor ROR-gamma, 4-[(~{E})-[3-[2-chloranyl-6-(trifluoromethyl)phenyl]-5-(1~{H}-pyrrol-3-yl)-1,2-oxazol-4-yl]methylideneamino]benzoic acid (3 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 | 28802.63 |
| Authors | de Vries, R.M.J.M.,Meijer, F.A.,Doveston, R.G.,Brunsveld, L. (deposition date: 2019-07-17, release date: 2019-12-25, Last modification date: 2024-01-24) |
| Primary citation | Meijer, F.A.,Doveston, R.G.,de Vries, R.M.J.M.,Vos, G.M.,Vos, A.A.A.,Leysen, S.,Scheepstra, M.,Ottmann, C.,Milroy, L.G.,Brunsveld, L. Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor gamma t (ROR gamma t) Inverse Agonists. J.Med.Chem., 63:241-259, 2020 Cited by PubMed Abstract: Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, (), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of was confirmed by biochemical experiments and cocrystallization with the RORγt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of RORγt. PubMed: 31821760DOI: 10.1021/acs.jmedchem.9b01372 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.61 Å) |
Structure validation
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