Structural Chemistry of the Histone Methyltransferases Cofactor Binding Site

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...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2011-03, Vol.51 (3), p.612-623
Main Authors: Campagna-Slater, Valérie, Mok, Man Wai, Nguyen, Kong T, Feher, Miklos, Najmanovich, Rafael, Schapira, Matthieu
Format: Article
Language:English
Subjects:
Binding Sites
Chromatin
Computational Chemistry
Condensed matter: electronic structure, electrical, magnetic, and optical properties
Electron states
Exact sciences and technology
Genes
Histone-Lysine N-Methyltransferase - chemistry
Humans
Methods of electronic structure calculations
Models, Molecular
Peptides
Phylogeny
Physics
Protein Conformation
Proteins
Sequence Alignment
Substrates
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Summary: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.
ISSN:1549-9596
1549-960X
DOI:10.1021/ci100479z