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| | <StructureSection load='5dtm' size='340' side='right'caption='[[5dtm]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='5dtm' size='340' side='right'caption='[[5dtm]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5dtm]] is a 2 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=5DTM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DTM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5dtm]] 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=5DTM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DTM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5F4:4-(2,6-DICHLOROBENZOYL)-N-METHYL-1H-PYRROLE-2-CARBOXAMIDE'>5F4</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]] 2.2Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5F4:4-(2,6-DICHLOROBENZOYL)-N-METHYL-1H-PYRROLE-2-CARBOXAMIDE'>5F4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5dtm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dtm OCA], [https://pdbe.org/5dtm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dtm RCSB], [https://www.ebi.ac.uk/pdbsum/5dtm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dtm ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5dtm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dtm OCA], [http://pdbe.org/5dtm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dtm RCSB], [http://www.ebi.ac.uk/pdbsum/5dtm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dtm ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone-lysine N-methyltransferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Be, C]] | + | [[Category: Be C]] |
| - | [[Category: Moebitz, H]] | + | [[Category: Moebitz H]] |
| - | [[Category: Scheufler, C]] | + | [[Category: Scheufler C]] |
| - | [[Category: Stauffer, F]] | + | [[Category: Stauffer F]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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 PubMed
Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.
Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.,Scheufler C, Mobitz H, Gaul C, Ragot C, Be C, Fernandez C, Beyer KS, Tiedt R, Stauffer F ACS Med Chem Lett. 2016 Jun 6;7(8):730-4. doi: 10.1021/acsmedchemlett.6b00168., eCollection 2016 Aug 11. PMID:27563394[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Scheufler C, Mobitz H, Gaul C, Ragot C, Be C, Fernandez C, Beyer KS, Tiedt R, Stauffer F. Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket. ACS Med Chem Lett. 2016 Jun 6;7(8):730-4. doi: 10.1021/acsmedchemlett.6b00168., eCollection 2016 Aug 11. PMID:27563394 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00168
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