6te6: Difference between revisions
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<StructureSection load='6te6' size='340' side='right'caption='[[6te6]], [[Resolution|resolution]] 1.98Å' scene=''> | <StructureSection load='6te6' size='340' side='right'caption='[[6te6]], [[Resolution|resolution]] 1.98Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6te6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TE6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TE6 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6te6]] 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=6TE6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TE6 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N4W:~{N}1-[(~{S})-(3-chlorophenyl)-pyridin-2-yl-methyl]-4-methylsulfonyl-~{N}2-pyrimidin-2-yl-benzene-1,2-diamine'>N4W</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N4W:~{N}1-[(~{S})-(3-chlorophenyl)-pyridin-2-yl-methyl]-4-methylsulfonyl-~{N}2-pyrimidin-2-yl-benzene-1,2-diamine'>N4W</scene></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='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='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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6te6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6te6 OCA], [http://pdbe.org/6te6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6te6 RCSB], [http://www.ebi.ac.uk/pdbsum/6te6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6te6 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6te6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6te6 OCA], [http://pdbe.org/6te6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6te6 RCSB], [http://www.ebi.ac.uk/pdbsum/6te6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6te6 ProSAT]</span></td></tr> | ||
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== 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. | [[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. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo. | |||
New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse.,Stauffer F, Weiss A, Scheufler C, Mobitz H, Ragot C, Beyer KS, Calkins K, Guthy D, Kiffe M, Van Eerdenbrugh B, Tiedt R, Gaul C ACS Med Chem Lett. 2019 Dec 4;10(12):1655-1660. doi:, 10.1021/acsmedchemlett.9b00452. eCollection 2019 Dec 12. PMID:31857842<ref>PMID:31857842</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6te6" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Histone-lysine N-methyltransferase]] | [[Category: Histone-lysine N-methyltransferase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Be, C]] | [[Category: Be, C]] | ||
Revision as of 15:17, 1 January 2020
Crystal structure of Dot1L in complex with an inhibitor (compound 3).Crystal structure of Dot1L in complex with an inhibitor (compound 3).
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 PubMedIn MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo. New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse.,Stauffer F, Weiss A, Scheufler C, Mobitz H, Ragot C, Beyer KS, Calkins K, Guthy D, Kiffe M, Van Eerdenbrugh B, Tiedt R, Gaul C ACS Med Chem Lett. 2019 Dec 4;10(12):1655-1660. doi:, 10.1021/acsmedchemlett.9b00452. eCollection 2019 Dec 12. PMID:31857842[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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