Abstract
A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via a combination of favourable cation-π interactions and the release of the high-energy water molecules that occupy the aromatic cage of reader proteins on the association with the trimethyllysine side chain. These results have implications in rational drug design by specifically targeting the aromatic cage of readers of trimethyllysine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyltransferases / chemistry*
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Amino Acids, Aromatic / chemistry
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Antigens, Nuclear / chemistry*
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Calorimetry
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Crystallography, X-Ray
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Epigenesis, Genetic
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Histone Code
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Histones / metabolism*
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Humans
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Jumonji Domain-Containing Histone Demethylases / chemistry*
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Lysine / analogs & derivatives*
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Lysine / chemistry
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Methylation
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Models, Molecular
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Molecular Dynamics Simulation
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Nerve Tissue Proteins / chemistry*
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Quaternary Ammonium Compounds
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Retinoblastoma-Binding Protein 2 / chemistry*
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TATA-Binding Protein Associated Factors
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Transcription Factor TFIID / chemistry*
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Transcription Factors / chemistry*
Substances
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Amino Acids, Aromatic
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Antigens, Nuclear
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Histones
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Nerve Tissue Proteins
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Quaternary Ammonium Compounds
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TAF3 protein, human
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TATA-Binding Protein Associated Factors
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Transcription Factor TFIID
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Transcription Factors
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fetal Alzheimer antigen
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trimethyllysine
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Jumonji Domain-Containing Histone Demethylases
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KDM5A protein, human
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Retinoblastoma-Binding Protein 2
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KDM4A protein, human
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Acetyltransferases
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Sgf29 protein, human
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Lysine