6te6 | pdb_00006te6

Crystal structure of Dot1L in complex with an inhibitor (compound 3).

spinqualitylabelsall models 6te6, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6te6 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: N4W Gene: DOT1L, KIAA1814, KMT4 (HUMAN) Activity: Histone-lysine N-methyltransferase, with EC number 2.1.1.43 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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