Insight into a novel p53 single point mutation (G389E) by Molecular Dynamics Simulations.

Abstract

The majority of inactivating mutations of p53 reside in the central core DNA binding domain of the protein. In this computational study, we investigated the structural effects of a novel p53 mutation (G389E), identified in a patient with congenital adrenal hyperplasia, which is located within the extreme C-terminal domain (CTD) of p53, an unstructured, flexible region (residues 367-393) of major importance for the regulation of the protein. Based on the three-dimensional structure of a carboxyl-terminal peptide of p53 in complex with the S100B protein, which is involved in regulation of the tumor suppressor activity, a model of wild type (WT) and mutant extreme CTD was developed by molecular modeling and molecular dynamics simulation. It was found that the G389E amino acid replacement has negligible effects on free p53 in solution whereas it significantly affects the interactions of p53 with the S100B protein. The results suggest that the observed mutation may interfere with p53 transcription activation and provide useful information for site-directed mutagenesis experiments.

• Authors: Davide Pirolli, Cristiana Carelli Alinovi, Ettore Capoluongo, Maria Antonia Satta, Paola Concolino, Bruno Giardina, Maria Cristina De Rosa
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 12 Issue 1 Pg. 128-40 (Dec 30 2010) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 21339981 (Publication Type: Journal Article)

Chemical References

• Tumor Suppressor Protein p53

Topics

• Adrenal Hyperplasia, Congenital (genetics)
• Amino Acid Sequence
• Binding Sites
• Humans
• Molecular Dynamics Simulation
• Molecular Sequence Data
• Point Mutation
• Protein Structure, Tertiary
• Tumor Suppressor Protein p53 (chemistry, genetics)