The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain

Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding...

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Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2013, Vol.31 (1), p.78-86
Main Authors: Pintus, S S, Ivanisenko, N V, Demenkov, P S, Ivanisenko, T V, Ramachandran, S, Kolchanov, N A, Ivanisenko, V A
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Binding Sites
Carrier Proteins - chemistry
Carrier Proteins - pharmacology
DNA - chemistry
DNA - metabolism
Molecular Dynamics Simulation
Mutation
Protein Conformation
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - metabolism
Zinc - chemistry
Zinc - metabolism
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Summary:Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding pocket can presumably exert an influence on Zn(2+) position in the Zn(2+)-p53 complex and thereby affect p53 binding to DNA. With these background considerations, our aim was to estimate the effect of the putative changes in the Zn(2+) position in its binding pocket due to the G245C and G245D substitutions on the conformation of the p53 DNA-binding motif. Statistical analysis of the molecular dynamics (MD) trajectories of the mutant p53-Zn(2+) complexes was used to detect significant deviations in conformation of the mutant p53 forms. MD simulations demonstrated that (1) the two substitutions in the Zn(2+)-binding pocket caused changes in the conformation of the p53 DNA-binding motif, as compared with the wild-type (WT) p53; (2) binding of Zn(2+) to the p53 mutant forms reduced the effect of the substitutions on conformational change; and (3) Zn(2+) binding in the normal position compensated the effect of the mutations on the conformation in comparison to the altered Zn(2+) position.
ISSN:1538-0254
DOI:10.1080/07391102.2012.691364