Molecular dynamics simulations of human DNA methyltransferase 3B with selective inhibitor nanaomycin A
Molecular dynamics simulations of human DNA methyltransferase 3B with selective inhibitor nanaomycin A
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DOI：
10.1016/j.jsb.2011.07.015
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发表时间：
2011-11-01
影响因子：
3
通讯作者：
Medina-Franco, Jose L.
中科院分区：
文献类型：
--
作者：
Caulfield, Thomas;Medina-Franco, Jose L.
DNA甲基转移酶（DNMT）参与基因组的表观遗传调控，是癌症和其他疾病治疗干预的有前途的靶点。到目前为止，关于DNMT分子动力学的信息非常有限。天然产物纳米霉素A是第一个诱导基因组去甲基化的DNMT 3B选择性抑制剂。在本文中，我们报告了长（>100 ns）的分子动力学模拟人类DNMT 3B结合纳米霉素A的存在和不存在的辅因子S-腺苷-L-甲硫氨酸（SAM）。我们得出结论，SAM有利于纳米霉素A与DNMT 3B的结合。纳米霉素A与DNMT 3B的关键相互作用涉及与Arg 731、Arg 733、Arg 832和催化Cys 651的持久相互作用。结果进一步支持了先前的假设，即纳米霉素A与参与甲基化机制的氨基酸残基具有关键的相互作用。这项工作是DNMT 3B的第一个分子动力学研究之一。这项工作的结果揭示了一个关键的表观遗传酶与小分子抑制剂的结构和结合识别过程。(C)2011 Elsevier Inc. All rights reserved.
DNA methyltransferases (DNMTs) are involved in epigenetic regulation of the genome and are promising targets for therapeutic intervention in cancer and other diseases. Until now, very limited information is available concerning the molecular dynamics of DNMTs. The natural product nanaomycin A is the first selective inhibitor of DNMT3B that induce genomic demethylation. Herein we report long (>100 ns) molecular dynamics simulations for human DNMT3B bound to nanaomycin A with and without the presence of the cofactor S-adenosyl-L-methionine (SAM). We concluded that SAM favors the binding of nanaomycin A to DNMT3B. Key interactions of nanaomycin A with DNMT3B involve long lasting interactions with Arg731, Arg733, Arg832, and the catalytic Cys651. Results further support the previous hypothesis that nanaomycin A has key interactions with amino acid residues involved in the mechanism of methylation. This work represents one of the first molecular dynamics studies of DNMT3B. Results of this work shed light on the structure and binding recognition process of a key epigenetic enzyme with a small molecule inhibitor. (C) 2011 Elsevier Inc. All rights reserved.