1. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
2. European Molecular Biology Laboratory (EMBL), c/o ILL, BP 156, 6 rue Jules Horowitz, 38043 Grenoble, France
3. These authors contributed equally to this work
4. Present address: Institute for Medical Radiobiology, University of Zürich, Zürich, Switzerland.
5. Present address: Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, Leiden , The Netherlands.

Correspondence to: Titia K. Sixma¹ Correspondence and requests for materials should be addressed to T.K.S. (e-mail: Email: sixma@nki.nl). Coordinates have been deposited in the protein data bank under accession number 1E3M.

Abstract

DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure at 2.2 Å of MutS from Escherichia coli bound to a GT mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutS (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure.

1. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
2. European Molecular Biology Laboratory (EMBL), c/o ILL, BP 156, 6 rue Jules Horowitz, 38043 Grenoble, France
3. These authors contributed equally to this work
4. Present address: Institute for Medical Radiobiology, University of Zürich, Zürich, Switzerland.
5. Present address: Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, Leiden , The Netherlands.

Correspondence to: Titia K. Sixma¹ Correspondence and requests for materials should be addressed to T.K.S. (e-mail: Email: sixma@nki.nl). Coordinates have been deposited in the protein data bank under accession number 1E3M.