4hra: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4hra]] 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=4HRA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HRA FirstGlance]. <br> | <table><tr><td colspan='2'>[[4hra]] 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=4HRA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HRA FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EP6:5-[{CIS-3-[2-(5-TERT-BUTYL-1H-BENZIMIDAZOL-2-YL)ETHYL]CYCLOBUTYL}(PROPAN-2-YL)AMINO]-5-DEOXYADENOSINE'>EP6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.15Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EP6:5-[{CIS-3-[2-(5-TERT-BUTYL-1H-BENZIMIDAZOL-2-YL)ETHYL]CYCLOBUTYL}(PROPAN-2-YL)AMINO]-5-DEOXYADENOSINE'>EP6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4hra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hra OCA], [https://pdbe.org/4hra PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hra RCSB], [https://www.ebi.ac.uk/pdbsum/4hra PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hra ProSAT]</span></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=4hra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hra OCA], [https://pdbe.org/4hra PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hra RCSB], [https://www.ebi.ac.uk/pdbsum/4hra PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hra ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 18:10, 20 September 2023
Crystal Structure of DOT1L in Complex with EPZ-5676Crystal Structure of DOT1L in Complex with EPZ-5676
Structural highlights
FunctionDOT1L_HUMAN Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. Publication Abstract from PubMedRearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness and there is thus a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has a Ki value of 80 pM, and demonstrates 37,000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous intravenous (IV) infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment for MLL-rearranged leukemia and is currently under clinical investigation. Potent inhibition of DOT1L as treatment for MLL-fusion leukemia.,Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, Waters NJ, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM Blood. 2013 Jun 25. PMID:23801631[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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