5DTR

Crystal structure of Dot1L in complex with inhibitor CPD5 [N-(2,6-dichlorophenyl)-4-methoxy-N-methylquinolin-6-amine]

Summary for 5DTR

• Entry DOI: 10.2210/pdb5dtr/pdb
• Descriptor: Histone-lysine N-methyltransferase, H3 lysine-79 specific, N-(2,6-dichlorophenyl)-4-methoxy-N-methylquinolin-6-amine (3 entities in total)
• Functional Keywords: inhibitor, complex, methyltransferase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q8TEK3
• Total number of polymer chains: 2
• Total formula weight: 77579.61

Authors

Scheufler, C.,Be, C.,Moebitz, H.,Stauffer, F. (deposition date: 2015-09-18, release date: 2016-06-15, Last modification date: 2024-01-10)

Primary citation

Scheufler, C.,Mobitz, H.,Gaul, C.,Ragot, C.,Be, C.,Fernandez, C.,Beyer, K.S.,Tiedt, R.,Stauffer, F.
Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.
Acs Med.Chem.Lett., 7:730-734, 2016

PubMed Abstract: Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.

PubMed: 27563394
DOI: 10.1021/acsmedchemlett.6b00168

Experimental method

X-RAY DIFFRACTION (2.34 Å)