5lod
Crystal structure of HhaI DNA methyltransferase in APO formCrystal structure of HhaI DNA methyltransferase in APO form
Structural highlights
FunctionMTH1_HAEPH This methylase recognizes the double-stranded sequence GCGC, causes specific methylation on C-2 on both strands, and protects the DNA from cleavage by the HhaI endonuclease. Publication Abstract from PubMedAIM: DNA methyltransferases (DNMTs) are important drug targets for epigenetic therapy of cancer. Nowadays, non-nucleoside DNMT inhibitors are in development to address high toxicity of nucleoside analogs. However, these compounds still have low activity in cancer cells and mode of action of these compounds remains unclear. MATERIALS & METHODS: In this work, we studied maleimide derivatives of RG108 by biochemical, structural and computational approaches to highlight their inhibition mechanism on DNMTs. RESULTS: Findings demonstrated a correlation between cytotoxicity on mesothelioma cells of these compounds and their inhibitory potency against DNMTs. Noncovalent and covalent docking studies, supported by crystallographic (apo structure of M.HhaI) and differential scanning fluorimetry assays, provided detailed insights into their mode of action and revealed essential residues for the stabilization of such compounds inside DNMTs. [Formula: see text]. Inhibition studies of DNA methyltransferases by maleimide derivatives of RG108 as non-nucleoside inhibitors.,Rondelet G, Fleury L, Faux C, Masson V, Dubois J, Arimondo PB, Willems L, Wouters J Future Med Chem. 2017 Aug 10. doi: 10.4155/fmc-2017-0074. PMID:28795598[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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