Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA

In vertebrates, the biological consequences of DNA methylation are often me diated by protein factors containing conserved methyl-CpG binding domains ( MBDs). Mutations in the MBD protein MeCP2 cause the neurodevelopmental dise ase Rett syndrome. We report here the solution structure of the MBD of the human methylation-dependent transcriptional regulator MBD1 bound to methyla ted BRA. DNA binding causes a loop in MBD1 to fold into a major and novel D NA binding interface. Recognition of the methyl groups and CG sequence at t he methylation site is due to five highly conserved residues that form a hy drophobic patch. The structure indicates how MBD may access nucleosomal DNA without encountering steric interference from core histones, and provides a basis to interpret mutations linked to Rett syndrome in MeCP2.