The crystal structure of DNA mismatch repair protein MutS binding to a G center dot T mismatch

DNA mismatch repair ensures genomic integrity on DNA replication. Recogniti on of a DNA mismatch by a dimeric MutS protein initiates a cascade of react ions and results in repair of the newly synthesized strand; however, detail s of the molecular mechanism remain controversial. Here we present the crys tal structure at 2.2 Angstrom of MutS from Escherichia coli bound to a G.T mismatch. The two MutS monomers have different conformations and form a het erodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive mi nor groove interactions causing unusual base pairing and kinking of the DNA . Nonspecific major groove DNA-binding domains from both monomers embrace t he DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutS alpha (MSH2/MSH6) tha t lead to hereditary predisposition for cancer, such as hereditary non-poly posis colorectal cancer, can be mapped to this crystal structure.