5m25
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Modulation of MLL1 Methyltransferase Activity== | |
| + | <StructureSection load='5m25' size='340' side='right'caption='[[5m25]], [[Resolution|resolution]] 2.43Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5m25]] 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=5M25 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M25 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]] 2.43Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7DU:(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-azanyl-3-oxidanyl-propanoyl]amino]propanoyl]amino]-5-carbamimidamido-~{N}-[(2~{S})-1-[[4-[(~{E})-[4-(hydroxymethyl)phenyl]diazenyl]phenyl]methylamino]-1-oxidanylidene-propan-2-yl]pentanamide'>7DU</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=5m25 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m25 OCA], [https://pdbe.org/5m25 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m25 RCSB], [https://www.ebi.ac.uk/pdbsum/5m25 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m25 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 == | ||
| + | We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein-protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity (Ki = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Importantly, the photoswitchable trans and cis conformers of the probe display a clear difference in their inhibition of MLL1. We further demonstrate that the designed photo-controllable azo-peptidomimetics affect the transcription of the MLL1-target gene Deptor, which regulates hematopoiesis and leukemogenesis, and inhibit the growth of leukemia cells. This strategy demonstrates the potential of photopharmacological inhibition of methyltransferase protein-protein interactions as a novel method for external epigenetic control, providing a new toolbox for controlling epigenetic states. | ||
| - | + | Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.,Albert L, Xu J, Wan R, Srinivasan V, Dou Y, Vazquez O Chem Sci. 2017 Jun 1;8(6):4612-4618. doi: 10.1039/c7sc00137a. Epub 2017 Apr 27. PMID:28970883<ref>PMID:28970883</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5m25" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Srinivasan V]] | ||
Current revision
Modulation of MLL1 Methyltransferase Activity
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