5drt: Difference between revisions
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==Crystal structure of Dot1L in complex with inhibitor CPD2 [2-(2-(5-((2-chlorophenoxy)methyl)-1H-tetrazol-1-yl)acetyl)-N-(4-chlorophenyl)hydrazinecarboxamide]== | |||
<StructureSection load='5drt' size='340' side='right'caption='[[5drt]], [[Resolution|resolution]] 2.69Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5drt]] 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=5DRT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DRT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.69Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5EG:2-({5-[(2-CHLOROPHENOXY)METHYL]-1H-TETRAZOL-1-YL}ACETYL)-N-(4-CHLOROPHENYL)HYDRAZINECARBOXAMIDE'>5EG</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=5drt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5drt OCA], [https://pdbe.org/5drt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5drt RCSB], [https://www.ebi.ac.uk/pdbsum/5drt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5drt 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors. | |||
Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.,Chen C, Zhu H, Stauffer F, Caravatti G, Vollmer S, Machauer R, Holzer P, Mobitz H, Scheufler C, Klumpp M, Tiedt R, Beyer KS, Calkins K, Guthy D, Kiffe M, Zhang J, Gaul C ACS Med Chem Lett. 2016 Jun 1;7(8):735-40. doi: 10.1021/acsmedchemlett.6b00167., eCollection 2016 Aug 11. PMID:27563395<ref>PMID:27563395</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5drt" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Be C]] | |||
[[Category: Gaul C]] | |||
[[Category: Moebitz H]] | |||
[[Category: Scheufler C]] | |||
Latest revision as of 00:57, 29 June 2023
Crystal structure of Dot1L in complex with inhibitor CPD2 [2-(2-(5-((2-chlorophenoxy)methyl)-1H-tetrazol-1-yl)acetyl)-N-(4-chlorophenyl)hydrazinecarboxamide]Crystal structure of Dot1L in complex with inhibitor CPD2 [2-(2-(5-((2-chlorophenoxy)methyl)-1H-tetrazol-1-yl)acetyl)-N-(4-chlorophenyl)hydrazinecarboxamide]
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 PubMedOncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors. Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.,Chen C, Zhu H, Stauffer F, Caravatti G, Vollmer S, Machauer R, Holzer P, Mobitz H, Scheufler C, Klumpp M, Tiedt R, Beyer KS, Calkins K, Guthy D, Kiffe M, Zhang J, Gaul C ACS Med Chem Lett. 2016 Jun 1;7(8):735-40. doi: 10.1021/acsmedchemlett.6b00167., eCollection 2016 Aug 11. PMID:27563395[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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