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==Crystal structure of human WD REPEAT DOMAIN 5 in complex with 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamide== | ==Crystal structure of human WD REPEAT DOMAIN 5 in complex with 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamide== | ||
<StructureSection load='4ia9' size='340' side='right' caption='[[4ia9]], [[Resolution|resolution]] 1.66Å' scene=''> | <StructureSection load='4ia9' size='340' side='right'caption='[[4ia9]], [[Resolution|resolution]] 1.66Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ia9]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4ia9]] 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=4IA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IA9 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IA9:2-CHLORO-4-FLUORO-3-METHYL-N-[2-(4-METHYLPIPERAZIN-1-YL)-5-NITROPHENYL]BENZAMIDE'>IA9</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IA9:2-CHLORO-4-FLUORO-3-METHYL-N-[2-(4-METHYLPIPERAZIN-1-YL)-5-NITROPHENYL]BENZAMIDE'>IA9</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=4ia9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ia9 OCA], [https://pdbe.org/4ia9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ia9 RCSB], [https://www.ebi.ac.uk/pdbsum/4ia9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ia9 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 20: | ||
==See Also== | ==See Also== | ||
*[[WD repeat | *[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Al-awar | [[Category: Large Structures]] | ||
[[Category: Arrowsmith | [[Category: Al-awar R]] | ||
[[Category: Bolshan | [[Category: Arrowsmith CH]] | ||
[[Category: Bountra | [[Category: Bolshan Y]] | ||
[[Category: Brown | [[Category: Bountra C]] | ||
[[Category: Dombrovski | [[Category: Brown PJ]] | ||
[[Category: Dong | [[Category: Dombrovski L]] | ||
[[Category: Edwards | [[Category: Dong A]] | ||
[[Category: Getlik | [[Category: Edwards AM]] | ||
[[Category: Hajian | [[Category: Getlik M]] | ||
[[Category: Kuznetsova | [[Category: Hajian T]] | ||
[[Category: Nguyen | [[Category: Kuznetsova E]] | ||
[[Category: Poda | [[Category: Nguyen KT]] | ||
[[Category: Poda G]] | |||
[[Category: Schapira | [[Category: Schapira M]] | ||
[[Category: Smil | [[Category: Smil D]] | ||
[[Category: Tempel | [[Category: Tempel W]] | ||
[[Category: Vedadi | [[Category: Vedadi M]] | ||
[[Category: Wasney | [[Category: Wasney GA]] | ||
[[Category: Wu | [[Category: Wu H]] | ||
Revision as of 11:52, 9 November 2022
Crystal structure of human WD REPEAT DOMAIN 5 in complex with 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamideCrystal structure of human WD REPEAT DOMAIN 5 in complex with 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamide
Structural highlights
FunctionWDR5_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.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 muM), leading to identification of more potent antagonist 47 (K dis = 0.3 muM). Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.,Bolshan Y, Getlik M, Kuznetsova E, Wasney GA, Hajian T, Poda G, Nguyen KT, Wu H, Dombrovski L, Dong A, Senisterra G, Schapira M, Arrowsmith CH, Brown PJ, Al-Awar R, Vedadi M, Smil D ACS Med Chem Lett. 2013 Feb 4;4(3):353-7. doi: 10.1021/ml300467n. eCollection, 2013 Mar 14. PMID:24900672[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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