5eni | pdb_00005eni

Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with compound-13 N11537 (SGC - Diamond I04-1 fragment screening)

spinqualitylabelsall models 5eni, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5eni 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 1.69Å Ligands: 5QA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PHIP_HUMAN Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization. Publication Abstract from PubMed Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.,Cox OB, Krojer T, Collins P, Monteiro O, Talon R, Bradley A, Fedorov O, Amin J, Marsden BD, Spencer J, von Delft F, Brennan PE Chem Sci. 2016 Mar 1;7(3):2322-2330. doi: 10.1039/c5sc03115j. Epub 2015 Dec 22. PMID:29910922 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also WD-repeat protein 3D structures

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