5m23: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 5m23 is ~~ON HOLD~~ ~~until Paper~~ Publication

==Modulation of MLL1 Methyltransferase Activity==

== Structural highlights ==

<table><tr><td colspan='2'>[[5m23]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M23 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M23 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7DC:4-[(~{E})-[4-[[[(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-azanyl-3-oxidanyl-propanoyl]amino]propanoyl]amino]-5-carbamimidamido-pentanoyl]amino]propanoyl]amino]methyl]phenyl]diazenyl]-~{N}-[(2~{S})-3-methyl-1-oxidanylidene-butan-2-yl]benzamide'>7DC</scene></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5m23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m23 OCA], [http://pdbe.org/5m23 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m23 RCSB], [http://www.ebi.ac.uk/pdbsum/5m23 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m23 ProSAT]</span></td></tr>

</table>

== Function ==

[[http://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>

== 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.

~~Authors~~:

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>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased Structures~~]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Srinivasan, V]]

[[Category: Mll1 methyltransferase peptide complex wdr5]]

[[Category: Transferase]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5m23 is ON HOLD  until Paper Publication
+==Modulation of MLL1 Methyltransferase Activity==
+<StructureSection load='5m23' size='340' side='right' caption='[[5m23]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5m23]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M23 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M23 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7DC:4-[(~{E})-[4-[[[(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-azanyl-3-oxidanyl-propanoyl]amino]propanoyl]amino]-5-carbamimidamido-pentanoyl]amino]propanoyl]amino]methyl]phenyl]diazenyl]-~{N}-[(2~{S})-3-methyl-1-oxidanylidene-butan-2-yl]benzamide'>7DC</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5m23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m23 OCA], [http://pdbe.org/5m23 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m23 RCSB], [http://www.ebi.ac.uk/pdbsum/5m23 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m23 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://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.
-Authors:
+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>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5m23" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Srinivasan, V]]
+[[Category: Mll1 methyltransferase peptide complex wdr5]]
+[[Category: Transferase]]