Abstract
MeCP2 is an essential transcriptional repressor that mediates gene silencing through binding to methylated DNA. Binding specificity has been thought to depend on hydrophobic interactions between cytosine methyl groups and a hydrophobic patch within the methyl-CpG-binding domain (MBD). X-ray analysis of a methylated DNA-MBD cocrystal reveals, however, that the methyl groups make contact with a predominantly hydrophilic surface that includes tightly bound water molecules. This suggests that MeCP2 recognizes hydration of the major groove of methylated DNA rather than cytosine methylation per se. The MeCP2-DNA complex also identifies a unique structural role for T158, the residue most commonly mutated in Rett syndrome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Brain-Derived Neurotrophic Factor / genetics
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CpG Islands*
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Crystallography, X-Ray
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DNA / chemistry*
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DNA / genetics
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DNA / metabolism*
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DNA Methylation
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Humans
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Macromolecular Substances / chemistry
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Macromolecular Substances / metabolism
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Methyl-CpG-Binding Protein 2 / chemistry*
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Methyl-CpG-Binding Protein 2 / genetics
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Methyl-CpG-Binding Protein 2 / metabolism*
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Models, Molecular
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Nucleic Acid Conformation*
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Promoter Regions, Genetic
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Protein Binding
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Protein Conformation*
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Rett Syndrome / genetics
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Sequence Alignment
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Thymine / chemistry
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Thymine / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Macromolecular Substances
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Methyl-CpG-Binding Protein 2
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DNA
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Thymine