In:
Philosophical Transactions of the Royal Society B: Biological Sciences, The Royal Society, Vol. 373, No. 1748 ( 2018-06-05), p. 20170072-
Abstract:
DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound 4 and its derivative 2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound 4 binds to the PRMT4 active site, displacing strongly the S -adenosyl- l -methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Type of Medium:
Online Resource
ISSN:
0962-8436
,
1471-2970
DOI:
10.1098/rstb.2017.0072
Language:
English
Publisher:
The Royal Society
Publication Date:
2018
detail.hit.zdb_id:
1462620-2
SSG:
12
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