7u9y

<StructureSection load='7u9y' size='340' side='right'caption='[[7u9y]], [[Resolution|resolution]] 1.90&Aring;' scene=''>

<table><tr><td colspan='2'>[[7u9y]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U9Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U9Y FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BEN:BENZAMIDINE'>BEN</scene>, <scene name='pdbligand=M4U:(5P)-2-[(3,5-dimethoxyphenyl)methyl]-7-[(2-methyl-1H-imidazol-1-yl)methyl]-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3,4-dihydroisoquinolin-1(2H)-one'>M4U</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=7u9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u9y OCA], [https://pdbe.org/7u9y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u9y RCSB], [https://www.ebi.ac.uk/pdbsum/7u9y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u9y ProSAT]</span></td></tr>

== 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>

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== Publication Abstract from PubMed ==

WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy to improve its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAR effort on the three pharmacophore units was combined to generate a new in vivo lead series. Importantly, this new series of compounds has picomolar binding affinity, improved cellular antiproliferative activity and selectivity, and increased kinetic aqueous solubility. They also exhibit a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oral bioavailability. Thus, these new leads are useful probes toward studying the effects of WDR5 inhibition.

 

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== References ==

[[Category: Rietz, T]]

[[Category: Transcription-transcription inhibitor complex]]