DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is one of several known DNA methyltransferase enzymes that play important role in gene expression modulation and cell differentiation. Malfunctions in DNMT3A can lead to a variety of diseases such as acute myeloid leukemia and myelodysplastic syndromes. DNMT3A decreases DNA transcription by precise methylation of short cytosine rich DNA regions called CpG islands, which subsequently leads to chromatin compression. To recognize regions in need of methylation, DNMT3A ‘reads’ various chemical modifications on the histone 3 (H3) tail, and these modifications can adjust the enzyme’s activity.<br/><br/>Recently, our collaborators identified modification X as a novel H3 modification, resulting in rise in DNMT3A’s activity. H3 Xylation is increased with above normal levels of X, which in its turn is associated with various disorders, but the role of H3 Xylation in the etiology of the disease is unknown. Our goal is to find small molecule ligands that would interfere with the DNMT3A interaction with Xylated H3 (H3X). To identify specific interactions to H3X, we compared atomic structures of DNMT3A bound to H3 and DNMT3A bound to H3X. Based on this analysis, we hypothesized that H3X promotes DNMT3A dimerization and subsequent increase of its enzymatic activity. Visual inspection and computational solvent mapping (FTMap server) allowed us to identify putative key residues in the DNMT3A/H3X interaction, as well as potential ‘druggable’ binding sites. We performed virtual screening of 405628 available for purchase fragment-like compounds from the ZINC library and identified 15 compounds that potentially disrupt the interactions of DNMT3A/H3X, but not the ones of DNMT3A/H3. We will purchase the selected compounds and test them experimentally. If successful, this study will provide chemical tools to disrupt the DNMT3A/H3X interaction, with hope to control the abnormal activity of DNMT3A, as well as reveal a novel mechanism by which Xylation regulates DNMT3A activity.

Structure-based prediction of small molecule modulators of DNMT3A

253rd National Meeting (2017)

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