6B31
Structure of RORgt in complex with a novel inverse agonist 2
Summary for 6B31
| Entry DOI | 10.2210/pdb6b31/pdb |
| Descriptor | Nuclear receptor ROR-gamma, (3S)-N~1~-(3-chloro-4-cyanophenyl)-N~5~-(1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3-methylpentanediamide (3 entities in total) |
| Functional Keywords | complex, inverse agonist, nuclear hormone receptor, signaling protein, signaling protein-agonist complex, signaling protein/agonist |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 54223.58 |
| Authors | Skene, R.J.,Hoffman, I. (deposition date: 2017-09-20, release date: 2018-08-01, Last modification date: 2024-03-13) |
| Primary citation | Fukase, Y.,Sato, A.,Tomata, Y.,Ochida, A.,Kono, M.,Yonemori, K.,Koga, K.,Okui, T.,Yamasaki, M.,Fujitani, Y.,Nakagawa, H.,Koyama, R.,Nakayama, M.,Skene, R.,Sang, B.C.,Hoffman, I.,Shirai, J.,Yamamoto, S. Identification of novel quinazolinedione derivatives as ROR gamma t inverse agonist. Bioorg. Med. Chem., 26:721-736, 2018 Cited by PubMed Abstract: Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed. PubMed: 29342416DOI: 10.1016/j.bmc.2017.12.039 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.18 Å) |
Structure validation
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