5dtq

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Crystal structure of Dot1L in complex with inhibitor CPD3 [(2,6-dichlorophenyl)(quinolin-6-yl)methanone]

Structural highlights

5dtq 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 2.61Å
Ligands:5F6
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

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.

Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.,Scheufler C, Mobitz H, Gaul C, Ragot C, Be C, Fernandez C, Beyer KS, Tiedt R, Stauffer F ACS Med Chem Lett. 2016 Jun 6;7(8):730-4. doi: 10.1021/acsmedchemlett.6b00168., eCollection 2016 Aug 11. PMID:27563394[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
11 reviews cite this structure
Inhibitors of Protein Methyltransferases and Demethylases.
Kaniskan et al. (2018)
10 more
7 other articles
No citations found

See Also

References

  1. ↑ Scheufler C, Mobitz H, Gaul C, Ragot C, Be C, Fernandez C, Beyer KS, 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. 2016 Jun 6;7(8):730-4. doi: 10.1021/acsmedchemlett.6b00168., eCollection 2016 Aug 11. PMID:27563394 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00168

Contents


PDB ID 5dtq

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