Structural Chemistry of the Histone Methyltransferases Cofactor Binding Site

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• 作者：Vale虂rie Campagna-Slater ; Man Wai Mok ; Kong T. Nguyen ; Miklos Feher ; Rafael Najmanovich ; Matthieu Schapira
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：March 28, 2011
• 年：2011
• 卷：51
• 期：3
• 页码：612-623
• 全文大小：1227K
• 年卷期：v.51,no.3(March 28, 2011)
• ISSN：1549-960X

文摘

Histone methyltransferases (HMTs) transfer a methyl group from the cofactor S-adenosyl methionine to lysine or arginine residues on histone tails, thereby regulating chromatin compaction, binding of effector proteins and gene transcription. HMTs constitute an emerging target class in diverse disease areas, and selective chemical probes are necessary for target validation. Potent and selective competitors of the substrate peptide have been reported, but the chemical tractability of the cofactor binding site is poorly understood. Here, a systematic analysis of this site across structures of 14 human HMTs or close homologues was conducted. The druggability, interaction hotspots, and diversity of the cofactor binding pocket were dissected. This analysis strongly suggests that this site is chemically tractable. General principles underlying tight binding and specific guidelines to achieve selective inhibition are presented.