6e22

Displacement of WDR5 from chromatin by a pharmacological WIN site inhibitor with picomolar affinity

spinqualitylabelsall models 6e22, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6e22 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 1.6Å Ligands: HLS, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function WDR5_HUMAN Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation. Publication Abstract from PubMed The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types. Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.,Aho ER, Wang J, Gogliotti RD, Howard GC, Phan J, Acharya P, Macdonald JD, Cheng K, Lorey SL, Lu B, Wenzel S, Foshage AM, Alvarado J, Wang F, Shaw JG, Zhao B, Weissmiller AM, Thomas LR, Vakoc CR, Hall MD, Hiebert SW, Liu Q, Stauffer SR, Fesik SW, Tansey WP Cell Rep. 2019 Mar 12;26(11):2916-2928.e13. doi: 10.1016/j.celrep.2019.02.047. PMID:30865883 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also WD-repeat protein 3D structures

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