4er5
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4er5]] 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=4ER5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ER5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4er5]] 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=4ER5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ER5 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QK: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'>0QK</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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]] 2.57Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QK: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'>0QK</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=4er5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4er5 OCA], [https://pdbe.org/4er5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4er5 RCSB], [https://www.ebi.ac.uk/pdbsum/4er5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4er5 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=4er5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4er5 OCA], [https://pdbe.org/4er5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4er5 RCSB], [https://www.ebi.ac.uk/pdbsum/4er5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4er5 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. | [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. | ||
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| - | 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> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4er5" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | *[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Crystal structure of human DOT1L in complex with 2 molecules of EPZ004777
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Categories: Homo sapiens | Large Structures | Arrowsmith CH | Bountra C | Bradner JE | Brown PJ | Edwards AM | Federation A | Li Y | Marineau J | Nguyen KT | Qi J | Schapira M | Scopton A | Tempel W | Vedadi M | Wernimont AK | Yu W
