Common conformational effects of p53 mutations

The tumor suppressor gene p53 has been identified as the most frequent targ et of genetic alterations in human cancers. Most of these mutations occur i n highly conserved regions in the DNA-binding core domain of the p53 protei n, suggesting that the amino acid residues in these regions are critical fo r maintaining normal p53 structure and function. We previously used molecul ar dynamics calculations to demonstrate that several amino acid substitutio ns in these regions that are induced by environmental carcinogens and found in human tumors produce certain common conformational changes in the mutan t proteins that differ substantially from the wild-type structure. In order to determine whether these conformational changes are consistent for other p53 mutants, we have now used molecular dynamics to determine the structur e of the DNA-binding core domain of seven other environmentally induced, ca ncer-related p53 mutants, namely His 175, Asp 245, Asn 245, Trp 248, Met 24 9, Ser 278, and Lys 286. The results indicate that all of these mutants dif fer substantially from the wild-type structure in certain discrete regions and that some of these conformational changes are similar for these mutants as well as those determined previously. The changes are also consistent wi th experimental evidence for alterations in structure in p53 mutants determ ined by epitope delectability using monoclonal antibodies directed against these regions of predicted conformational change.