Mechanism of mismatch recognition revealed by human MutSβ bound to unpaired DNA loops

Nat Struct Mol Biol. 2011 Dec 18;19(1):72-8. doi: 10.1038/nsmb.2175.


DNA mismatch repair corrects replication errors, thus reducing mutation rates and microsatellite instability. Genetic defects in this pathway cause Lynch syndrome and various cancers in humans. Binding of a mispaired or unpaired base by bacterial MutS and eukaryotic MutSα is well characterized. We report here crystal structures of human MutSβ in complex with DNA containing insertion-deletion loops (IDL) of two, three, four or six unpaired nucleotides. In contrast to eukaryotic MutSα and bacterial MutS, which bind the base of a mismatched nucleotide, MutSβ binds three phosphates in an IDL. DNA is severely bent at the IDL; unpaired bases are flipped out into the major groove and partially exposed to solvent. A normal downstream base pair can become unpaired; a single unpaired base can thereby be converted to an IDL of two nucleotides and recognized by MutSβ. The C-terminal dimerization domains form an integral part of the MutS structure and coordinate asymmetrical ATP hydrolysis by Msh2 and Msh3 with mismatch binding to signal for repair.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Binding, Competitive
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA Mismatch Repair*
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Models, Genetic
  • Models, Molecular
  • Molecular Sequence Data
  • MutS DNA Mismatch-Binding Protein / chemistry
  • MutS DNA Mismatch-Binding Protein / genetics
  • MutS DNA Mismatch-Binding Protein / metabolism
  • MutS Homolog 2 Protein / chemistry*
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / metabolism
  • MutS Homolog 3 Protein
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • DNA-Binding Proteins
  • MSH3 protein, human
  • MutS Homolog 3 Protein
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • DNA
  • Adenosine Triphosphatases
  • MSH2 protein, human
  • MutS DNA Mismatch-Binding Protein
  • MutS Homolog 2 Protein

Associated data

  • PDB/3THW
  • PDB/3THX
  • PDB/3THY
  • PDB/3THZ