Mutations in the genes whose products participate in DNA mismatch repa
ir underlie the increased risk of cancer in families with. hereditary
nonpolyposis colon carcinoma. Mutations in hMSH2 account for approxima
tely 50% of the mutations found in these families, We sought to predic
t the 3-dimensional structure of hMSH2 by identifying structural homol
ogues using prediction-based threading and by computer modeling using
information from these putative structurally related proteins. Predict
ion-based threading identified three candidate structural homologues:
glycogen phosphorylase (gpb), a 70 kDa soluble lyric transglycosylase,
and ribonucleotide reductase protein R1. An independent approach util
izing a potential-based threading program also identified gpb as a str
uctural homologue. The models based on the structures of these protein
s suggest that the ATP binding domain and helix-turn-helix domain are
exposed on the outside of the protein, All known bacterial MutS and hM
SH2 mutations appear to be clustered in similar vicinities in the theo
retical models of hMSH2; the major site is within the ATP binding doma
in and near the carboxyl-terminal end, whereas a smaller number map to
the region coding for exon 5 and the amino-terminal domain. All point
mutations also appear to affect amino acids that are exposed on the o
utside surface of the protein.