5g44

Ligand complex of RORg LBD

spinqualitylabelsall models 5g44, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5g44 is a 2 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 1.84Å Ligands: DMS, I6G, NA, SWX, YTZ 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 The retinoic-acid-related orphan receptor gamma t (RORgammat), as a master regulator of Th17 cell pathology, has become an attractive target for small-molecule drug discovery for the treatment of Th17-cell-related autoimmune diseases. A crystallographic fragment screening was carried out for RORgammat using the ligand binding domain. An overall hit rate of 5.5 % was obtained by screening 384 compounds in 96 cocktails. Five distinct hotspots were identified, and four regions of anchoring polar interactions were observed. In addition, significant induced fit was found for the binding of several fragments. Strikingly, a simultaneous binding of three fragments was revealed which presents interesting features including pi-pi stacking, multiple hydrogen bonds to the protein, and significant induced fit. Overall, the results offer a complete mapping of the ligand binding pocket and provide valuable inspiration in structure-based design for RORgammat lead generation and optimization. The crystallographic screening also resulted in fragment hits that bind at the surface away from the ligand binding pocket. This surface site is near the plausible dimer interface by analogy with other nuclear receptor systems, which can provide initial hints to explore alternative ways to modulate RORgammat through protein-protein interactions. Fragment Screening of RORgammat Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments.,Xue Y, Guo H, Hillertz P ChemMedChem. 2016 Jul 19. doi: 10.1002/cmdc.201600242. PMID:27432277 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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