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==Crystal Structure of Human DOT1L in Complex with a Selective Inhibitor== | ==Crystal Structure of Human DOT1L in Complex with a Selective Inhibitor== | ||
<StructureSection load='3sr4' size='340' side='right' caption='[[3sr4]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='3sr4' size='340' side='right'caption='[[3sr4]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3sr4]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3sr4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SR4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SR4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TT8:(2S)-2-AZANYL-4-[[(2S,3S,4R,5R)-5-[6-(METHYLAMINO)PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYLSULFANYL]BUTANOIC+ACID'>TT8</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TT8:(2S)-2-AZANYL-4-[[(2S,3S,4R,5R)-5-[6-(METHYLAMINO)PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYLSULFANYL]BUTANOIC+ACID'>TT8</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nw3|1nw3]], [[3qow|3qow]], [[3qox|3qox]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1nw3|1nw3]], [[3qow|3qow]], [[3qox|3qox]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DOT1L, KIAA1814, KMT4 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DOT1L, KIAA1814, KMT4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [https://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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3sr4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sr4 OCA], [https://pdbe.org/3sr4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sr4 RCSB], [https://www.ebi.ac.uk/pdbsum/3sr4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sr4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://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. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 23: | ||
==See Also== | ==See Also== | ||
*[[Histone methyltransferase|Histone methyltransferase]] | *[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 30: | Line 30: | ||
[[Category: Histone-lysine N-methyltransferase]] | [[Category: Histone-lysine N-methyltransferase]] | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Chen, P]] | [[Category: Chen, P]] | ||
[[Category: Diao, J]] | [[Category: Diao, J]] | ||
Revision as of 11:07, 29 June 2022
Crystal Structure of Human DOT1L in Complex with a Selective InhibitorCrystal Structure of Human DOT1L in Complex with a Selective Inhibitor
Structural highlights
Function[DOT1L_HUMAN] Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. Publication Abstract from PubMedHistone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure and mechanism based design to discover several potent inhibitors of DOT1L with IC50 values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The x-ray crystal structure of a DOT1L:inhibitor complex reveals that N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease. Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis and Crystallographic Studies.,Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y J Am Chem Soc. 2011 Sep 21. PMID:21936531[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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