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4er6

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Crystal structure of human DOT1L in complex with inhibitor SGC0946

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 ==Crystal structure of human DOT1L in complex with inhibitor SGC0946==
-<StructureSection load='4er6' size='340' side='right' caption='[[4er6]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='4er6' size='340' side='right'caption='[[4er6]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4er6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ER6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ER6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4er6]] 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=4ER6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ER6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AW2:5-BROMO-7-{5-[(3-{[(4-TERT-BUTYLPHENYL)CARBAMOYL]AMINO}PROPYL)(PROPAN-2-YL)AMINO]-5-DEOXY-BETA-D-RIBOFURANOSYL}-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE'>AW2</scene>, <scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 2.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4eqz|4eqz]], [[4er0|4er0]], [[4er3|4er3]], [[4er5|4er5]], [[4er7|4er7]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AW2:5-BROMO-7-{5-[(3-{[(4-TERT-BUTYLPHENYL)CARBAMOYL]AMINO}PROPYL)(PROPAN-2-YL)AMINO]-5-DEOXY-BETA-D-RIBOFURANOSYL}-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE'>AW2</scene>, <scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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 HUMAN])</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=4er6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4er6 OCA], [https://pdbe.org/4er6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4er6 RCSB], [https://www.ebi.ac.uk/pdbsum/4er6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4er6 ProSAT]</span></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=4er6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4er6 OCA], [http://pdbe.org/4er6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4er6 RCSB], [http://www.ebi.ac.uk/pdbsum/4er6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4er6 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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.
+[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;">
-== Publication Abstract from PubMed ==
-Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.
-Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.,Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, Marineau JJ, Qi J, Barsyte-Lovejoy D, Yi J, Marcellus R, Iacob RE, Engen JR, Griffin C, Aman A, Wienholds E, Li F, Pineda J, Estiu G, Shatseva T, Hajian T, Al-Awar R, Dick JE, Vedadi M, Brown PJ, Arrowsmith CH, Bradner JE, Schapira M Nat Commun. 2012;3:1288. doi: 10.1038/ncomms2304. PMID:23250418<ref>PMID:23250418</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 4er6" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Histone methyltransferase|Histone methyltransferase]]
+*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
-== References ==
-<references/>
 __TOC__
 </StructureSection>
-[[Category: Histone-lysine N-methyltransferase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
+[[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Bradner, J E]]
+[[Category: Bradner JE]]
-[[Category: Brown, P J]]
+[[Category: Brown PJ]]
-[[Category: Edwards, A M]]
+[[Category: Edwards AM]]
-[[Category: Li, Y]]
+[[Category: Li Y]]
-[[Category: Nguyen, K T]]
+[[Category: Nguyen KT]]
-[[Category: Structural genomic]]
+[[Category: Schapira M]]
-[[Category: Schapira, M]]
+[[Category: Scopton A]]
-[[Category: Scopton, A]]
+[[Category: Tempel W]]
-[[Category: Tempel, W]]
+[[Category: Vedadi M]]
-[[Category: Vedadi, M]]
+[[Category: Wernimont AK]]
-[[Category: Wernimont, A K]]
+[[Category: Yu W]]
-[[Category: Yu, W]]
-[[Category: Epigenetic]]
-[[Category: Histone]]
-[[Category: Methyltransferase]]
-[[Category: Sgc]]
-[[Category: Transferase-transferase inhibitor complex]]

4er6

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Crystal structure of human DOT1L in complex with inhibitor SGC0946

Structural highlights

Function

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