4gm8
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human WD repeat domain 5 with compound MM-102== | |
| + | <StructureSection load='4gm8' size='340' side='right'caption='[[4gm8]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4gm8]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GM8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GM8 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.601Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0XL:2-AMINO-2-ETHYLBUTANOIC+ACID'>0XL</scene>, <scene name='pdbligand=0XN:1,1-BIS(4-FLUOROPHENYL)METHANAMINE'>0XN</scene>, <scene name='pdbligand=AC5:1-AMINOCYCLOPENTANECARBOXYLIC+ACID'>AC5</scene>, <scene name='pdbligand=ALQ:2-METHYL-PROPIONIC+ACID'>ALQ</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gm8 OCA], [https://pdbe.org/4gm8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gm8 RCSB], [https://www.ebi.ac.uk/pdbsum/4gm8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gm8 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/WDR5_HUMAN 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.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins. | ||
| - | + | High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.,Karatas H, Townsend EC, Cao F, Chen Y, Bernard D, Liu L, Lei M, Dou Y, Wang S J Am Chem Soc. 2013 Jan 16;135(2):669-82. doi: 10.1021/ja306028q. Epub 2012 Dec, 27. PMID:23210835<ref>PMID:23210835</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 4gm8" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bernard D]] | ||
| + | [[Category: Cao F]] | ||
| + | [[Category: Chen Y]] | ||
| + | [[Category: Dou Y]] | ||
| + | [[Category: Karatas H]] | ||
| + | [[Category: Lei M]] | ||
| + | [[Category: Liu L]] | ||
| + | [[Category: Townsend EC]] | ||
| + | [[Category: Wang S]] | ||
Current revision
Crystal structure of human WD repeat domain 5 with compound MM-102
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Categories: Homo sapiens | Large Structures | Bernard D | Cao F | Chen Y | Dou Y | Karatas H | Lei M | Liu L | Townsend EC | Wang S
