4er3: Difference between revisions
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==Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777== | ==Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777== | ||
<StructureSection load='4er3' size='340' side='right' caption='[[4er3]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='4er3' size='340' side='right'caption='[[4er3]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4er3]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4er3]] 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=4ER3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ER3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene | </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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4er3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4er3 OCA], [https://pdbe.org/4er3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4er3 RCSB], [https://www.ebi.ac.uk/pdbsum/4er3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4er3 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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 20: | ||
==See Also== | ==See Also== | ||
*[[Histone methyltransferase|Histone methyltransferase]] | *[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Arrowsmith | [[Category: Arrowsmith CH]] | ||
[[Category: Bountra | [[Category: Bountra C]] | ||
[[Category: Bradner | [[Category: Bradner JE]] | ||
[[Category: Brown | [[Category: Brown PJ]] | ||
[[Category: Edwards | [[Category: Edwards AM]] | ||
[[Category: Federation | [[Category: Federation A]] | ||
[[Category: Li | [[Category: Li Y]] | ||
[[Category: Marineau | [[Category: Marineau J]] | ||
[[Category: Nguyen | [[Category: Nguyen KT]] | ||
[[Category: Qi | [[Category: Qi J]] | ||
[[Category: Schapira M]] | |||
[[Category: Schapira | [[Category: Scopton A]] | ||
[[Category: Scopton | [[Category: Tempel W]] | ||
[[Category: Tempel | [[Category: Vedadi M]] | ||
[[Category: Vedadi | [[Category: Wernimont AK]] | ||
[[Category: Wernimont | [[Category: Yu W]] | ||
[[Category: Yu | |||
Revision as of 07:09, 7 October 2022
Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777
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 PubMedSelective 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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