5drt | pdb_00005drt

Crystal structure of Dot1L in complex with inhibitor CPD2 [2-(2-(5-((2-chlorophenoxy)methyl)-1H-tetrazol-1-yl)acetyl)-N-(4-chlorophenyl)hydrazinecarboxamide]

spinqualitylabelsall models 5drt, resolution 2.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5drt is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.69Å Ligands: 5EG, K Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone methyltransferase 3D structures

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