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3sx0

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Crystal structure of Dot1l in complex with a brominated SAH analog

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Retrieved from "http://52.214.119.220/wiki/index.php/3sx0"

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 <StructureSection load='3sx0' size='340' side='right'caption='[[3sx0]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3sx0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SX0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SX0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3sx0]] 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=3SX0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SX0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SX0:(2S)-2-AMINO-4-({[(2S,3S,4R,5R)-5-(4-AMINO-5-BROMO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL}SULFANYL)BUTANOIC+ACID+(NON-PREFERRED+NAME)'>SX0</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]] 2.28&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DOT1L, KIAA1814, KMT4 ([https://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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SX0:(2S)-2-AMINO-4-({[(2S,3S,4R,5R)-5-(4-AMINO-5-BROMO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL}SULFANYL)BUTANOIC+ACID+(NON-PREFERRED+NAME)'>SX0</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [https://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=3sx0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sx0 OCA], [https://pdbe.org/3sx0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sx0 RCSB], [https://www.ebi.ac.uk/pdbsum/3sx0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sx0 ProSAT]</span></td></tr>
 </table>
 == 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 ==
-Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia.
-Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.,Yu W, Smil D, Li F, Tempel W, Fedorov O, Nguyen KT, Bolshan Y, Al-Awar R, Knapp S, Arrowsmith CH, Vedadi M, Brown PJ, Schapira M Bioorg Med Chem. 2013 Apr 1;21(7):1787-1794. doi: 10.1016/j.bmc.2013.01.049. Epub, 2013 Jan 30. PMID:23433670<ref>PMID:23433670</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 3sx0" style="background-color:#fffaf0;"></div>
 ==See Also==
 *[[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: 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: Smil D]]
-[[Category: Smil, D]]
+[[Category: Tempel W]]
-[[Category: Tempel, W]]
+[[Category: Vedadi M]]
-[[Category: Vedadi, M]]
+[[Category: Weigelt J]]
-[[Category: Weigelt, J]]
+[[Category: Wernimont AK]]
-[[Category: Wernimont, A K]]
+[[Category: Yu W]]
-[[Category: Yu, W]]
-[[Category: Epigenetic]]
-[[Category: Histone]]
-[[Category: Methyltransferase]]
-[[Category: Sgc]]
-[[Category: Transferase]]

3sx0

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Crystal structure of Dot1l in complex with a brominated SAH analog

Structural highlights

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