5mw4
From Proteopedia
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==Crystal structure of Dot1L in complex with inhibitor CPD7 [N-(3-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)amino)propyl)-2-(3-(2-chloro-3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)ureido)acetamide]== | ==Crystal structure of Dot1L in complex with inhibitor CPD7 [N-(3-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)amino)propyl)-2-(3-(2-chloro-3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)ureido)acetamide]== | ||
| - | <StructureSection load='5mw4' size='340' side='right' caption='[[5mw4]], [[Resolution|resolution]] 2.19Å' scene=''> | + | <StructureSection load='5mw4' size='340' side='right'caption='[[5mw4]], [[Resolution|resolution]] 2.19Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5mw4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MW4 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5mw4]] is a 2 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=5MW4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MW4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5JU:N~2~-{[2-CHLORO-3-(2-METHYLPYRIDIN-3-YL)-1-BENZOTHIOPHEN-5-YL]CARBAMOYL}-N-(3-{METHYL[(3R)-1-(5H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDIN-3-YL]AMINO}PROPYL)GLYCINAMIDE'>5JU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.19Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5JU:N~2~-{[2-CHLORO-3-(2-METHYLPYRIDIN-3-YL)-1-BENZOTHIOPHEN-5-YL]CARBAMOYL}-N-(3-{METHYL[(3R)-1-(5H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDIN-3-YL]AMINO}PROPYL)GLYCINAMIDE'>5JU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5mw4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mw4 OCA], [https://pdbe.org/5mw4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mw4 RCSB], [https://www.ebi.ac.uk/pdbsum/5mw4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mw4 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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor. | ||
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| + | Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.,Mobitz H, Machauer R, Holzer P, Vaupel A, Stauffer F, Ragot C, Caravatti G, Scheufler C, Fernandez C, Hommel U, Tiedt R, Beyer KS, Chen C, Zhu H, Gaul C ACS Med Chem Lett. 2017 Feb 14;8(3):338-343. doi: 10.1021/acsmedchemlett.6b00519., eCollection 2017 Mar 9. PMID:28337327<ref>PMID:28337327</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5mw4" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: Be | + | [[Category: Large Structures]] |
| - | [[Category: Gaul | + | [[Category: Be C]] |
| - | [[Category: Koch | + | [[Category: Gaul C]] |
| - | [[Category: Moebitz | + | [[Category: Koch E]] |
| - | [[Category: Scheufler | + | [[Category: Moebitz H]] |
| - | [[Category: Stauffer | + | [[Category: Scheufler C]] |
| - | + | [[Category: Stauffer F]] | |
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Current revision
Crystal structure of Dot1L in complex with inhibitor CPD7 [N-(3-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)amino)propyl)-2-(3-(2-chloro-3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)ureido)acetamide]
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Categories: Homo sapiens | Large Structures | Be C | Gaul C | Koch E | Moebitz H | Scheufler C | Stauffer F
