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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.

Original publication




Journal article


Mol Cell

Publication Date





525 - 531


Amino Acid Sequence, Animals, Brain-Derived Neurotrophic Factor, CpG Islands, Crystallography, X-Ray, DNA, DNA Methylation, Humans, Macromolecular Substances, Methyl-CpG-Binding Protein 2, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Nucleic Acid Conformation, Promoter Regions, Genetic, Protein Binding, Protein Conformation, Rett Syndrome, Sequence Alignment, Thymine