5apk
Ligand complex of RORg LBD
Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedRORgammat, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORgamma), 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 RORgamma 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 RORgamma-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 RORgamma-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-benzoxaze pin-6-amine ) and structures of other known RORgamma modulators. Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (T 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORgamma.,Olsson RI, Xue Y, von Berg S, Aagaard A, McPheat J, Hansson EL, Bernstrom J, Hansson P, Jirholt J, Grindebacke H, Leffler A, Chen R, Xiong Y, Ge H, Hansson TG, Narjes F ChemMedChem. 2015 Nov 10. doi: 10.1002/cmdc.201500432. PMID:26553345[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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