4wqp

Crystal structure of RORc in complex with a benzyl sulfonamide inverse agonist

spinqualitylabelsall models 4wqp, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wqp is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.99Å Ligands: 3SX, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RORG_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 PubMed A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled. Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.,Rene O, Fauber BP, Boenig Gde L, Burton B, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, Kiefer JR, Liimatta M, Lockey P, Norman M, Ouyang W, Wallweber HA, Wong H ACS Med Chem Lett. 2014 Dec 4;6(3):276-81. doi: 10.1021/ml500420y. eCollection, 2015 Mar 12. PMID:25815138 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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