4ypq | pdb_00004ypq

Crystal structure of the ROR(gamma)t ligand binding domain in complex with 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)benzoic acid

spinqualitylabelsall models 4ypq, resolution 2.32Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ypq is a 1 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 2.32Å Ligands: 4F1, MG 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 RORgammat is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORgammat. Co-crystallization of the ligand binding domain (LBD) of RORgammat with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORgammat LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORgammat function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORgammat ligands. This brings forward an approach to target RORgammat for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors. Identification of an allosteric binding site for RORgammat inhibition.,Scheepstra M, Leysen S, van Almen GC, Miller JR, Piesvaux J, Kutilek V, van Eenennaam H, Zhang H, Barr K, Nagpal S, Soisson SM, Kornienko M, Wiley K, Elsen N, Sharma S, Correll CC, Trotter BW, van der Stelt M, Oubrie A, Ottmann C, Parthasarathy G, Brunsveld L Nat Commun. 2015 Dec 7;6:8833. doi: 10.1038/ncomms9833. PMID:26640126 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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