6te6

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

Structural highlights

6te6 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 1.98Å
Ligands:N4W
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[1]

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

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Citations
5 reviews cite this structure
Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors.
Alexandrova et al. (2022)
4 more
4 other articles
No citations found

See Also

References

  1. ↑ 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. New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse. ACS Med Chem Lett. 2019 Dec 4;10(12):1655-1660. doi:, 10.1021/acsmedchemlett.9b00452. eCollection 2019 Dec 12. PMID:31857842 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00452

Contents


PDB ID 6te6

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OCA

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