4hra: Difference between revisions

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-{{STRUCTURE_4hra|  PDB=4hra  |  SCENE=  }}
+==Crystal Structure of DOT1L in Complex with EPZ-5676==
-===Crystal Structure of DOT1L in Complex with EPZ-5676===
+<StructureSection load='4hra' size='340' side='right' caption='[[4hra]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
-{{ABSTRACT_PUBMED_23801631}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4hra]] is a 1 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HRA FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ekg|4ekg]], [[4eki|4eki]], [[4ek9|4ek9]], [[3qow|3qow]], [[3qox|3qox]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DOT1L, KIAA1814, KMT4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></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=4hra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hra OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hra RCSB], [http://www.ebi.ac.uk/pdbsum/4hra PDBsum]</span></td></tr>
+</table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Rearrangements 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.
-==Function==
+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<ref>PMID:23801631</ref>
-[[http://www.uniprot.org/uniprot/DOT1L_HUMAN DOT1L_HUMAN]] Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA.
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[4hra]] is a 1 chain structure with sequence from [http://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].
+</div>
-==Reference==
+==See Also==
-<ref group="xtra">PMID:023801631</ref><references group="xtra"/><references/>
+*[[Histone methyltransferase|Histone methyltransferase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Histone-lysine N-methyltransferase]]
 [[Category: Homo sapiens]]
-[[Category: Jin, L.]]
+[[Category: Jin, L]]
 [[Category: Histone lysine methyltransferase]]
 [[Category: Transferase]]
 [[Category: Transferase-transferase inhibitor complex]]