5APH

Ligand complex of RORg LBD

Summary for 5APH

• Entry DOI: 10.2210/pdb5aph/pdb
• Related: 5APJ 5APK
• Descriptor: NUCLEAR RECEPTOR ROR-GAMMA, NUCLEAR RECEPTOR COACTIVATOR 2, N-(2-FLUOROPHENYL)-4-[(4-FLUOROPHENYL)SULFONYL]-2,3,4,5-TETRAHYDRO-1,4-BENZOXAZEPIN-6-AMINE, ... (5 entities in total)
• Functional Keywords: transcription, rorg ligand, rorg agonist, structure-based design
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus : P51449 E7EWM1
• Total number of polymer chains: 2
• Total formula weight: 32888.76

Authors

Xue, Y.,Aagaard, A.,Narjes, F. (deposition date: 2015-09-16, release date: 2015-11-25, Last modification date: 2024-01-10)

Primary citation

Olsson, R.I.,Xue, Y.,von Berg, S.,Aagaard, A.,McPheat, J.,Hansson, E.L.,Bernstrom, J.,Hansson, P.,Jirholt, J.,Grindebacke, H.,Leffler, A.,Chen, R.,Xiong, Y.,Ge, H.,Hansson, T.G.,Narjes, F.
Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (TH 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor ROR gamma.
ChemMedChem, 11:207-216, 2016

PubMed Abstract: RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.

PubMed: 26553345
DOI: 10.1002/cmdc.201500432

Experimental method

X-RAY DIFFRACTION (1.54 Å)