DNMT1, the major maintenance DNA methyltransferase in animals, helps to regulate 
gene expression, genome imprinting, and X-chromosome inactivation. We report on 
the crystal structure of a productive covalent mouse DNMT1(731-1602)-DNA complex 
containing a central hemimethylated CpG site. The methyl group of methylcytosine 
is positioned within a shallow hydrophobic concave surface, whereas the cytosine 
on the target strand is looped out and covalently anchored within the catalytic 
pocket. The DNA is distorted at the hemimethylated CpG step, with side chains 
from catalytic and recognition loops inserting through both grooves to fill an 
intercalation-type cavity associated with a dual base flip-out on partner 
strands. Structural and biochemical data establish how a combination of active 
and autoinhibitory mechanisms ensures the high fidelity of DNMT1-mediated 
maintenance DNA methylation.