View source for 5eap


==Crystal structure of human WDR5 in complex with compound 9e==
<StructureSection load='5eap' size='340' side='right'caption='[[5eap]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5eap]] is a 1 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=5EAP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EAP 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]] 1.73&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5MO:N-[5-(2,3-DIHYDRO-1-BENZOFURAN-5-YL)-2-(4-METHYLPIPERAZIN-1-YL)PHENYL]-3-METHYLBENZAMIDE'>5MO</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=5eap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eap OCA], [https://pdbe.org/5eap PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eap RCSB], [https://www.ebi.ac.uk/pdbsum/5eap PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eap 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 ==
WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp &lt; 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4 -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.

Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).,Getlik M, Smil D, Zepeda-Velazquez C, Bolshan Y, Poda G, Wu H, Dong A, Kuznetsova E, Marcellus R, Senisterra G, Dombrovski L, Hajian T, Kiyota T, Schapira M, Arrowsmith CH, Brown PJ, Vedadi M, Al-Awar R J Med Chem. 2016 Mar 24;59(6):2478-96. doi: 10.1021/acs.jmedchem.5b01630. Epub, 2016 Mar 9. PMID:26958703<ref>PMID:26958703</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5eap" 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: AL-AWAR R]]
[[Category: Arrowsmith CH]]
[[Category: BOLSHAN Y]]
[[Category: BROWN PJ]]
[[Category: Bountra C]]
[[Category: DOMBROVSKI L]]
[[Category: DONG A]]
[[Category: Edwards AM]]
[[Category: GETLIK M]]
[[Category: PODA G]]
[[Category: SCHAPIRA M]]
[[Category: SENISTERRA G]]
[[Category: SMIL D]]
[[Category: VEDADI M]]
[[Category: WALKER JR]]
[[Category: WU H]]