Common conformational effects of p53 mutations.
The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Most of these mutations occur in highly conserved regions in the DNA-binding core domain of the p53 protein, suggesting that the amino acid residues in these regions are critical for maintaining normal p53 structure and function. We previously used molecular dynamics calculations to demonstrate that several amino acid substitutions in these regions that are induced by environmental carcinogens and found in human tumors produce certain common conformational changes in the mutant 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 structure of the DNA-binding core domain of seven other environmentally induced, cancer-related p53 mutants, namely His 175, Asp 245, Asn 245, Trp 248, Met 249, Ser 278, and Lys 286. The results indicate that all of these mutants differ 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 with experimental evidence for alterations in structure in p53 mutants determined by epitope detectability using monoclonal antibodies directed against these regions of predicted conformational change.
Chen
J M
JM
Tularik Inc., South San Francisco, CA 94080, USA.
Rosal
R
R
Smith
S
S
Pincus
M R
MR
Brandt-Rauf
P W
PW
D019943:Amino Acid Substitution / Q000235:genetics*; D000911:Antibodies, Monoclonal; D001665:Binding Sites / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000502:physiology; D057927:Hydrophobic and Hydrophilic Interactions; D016296:Mutagenesis / Q000235:genetics*; D011487:Protein Conformation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics*; D015032:Zinc / Q000502:physiology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D016159:Tumor Suppressor Protein p53; D015032:Zinc