期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 31, 期 1, 页码 78-86出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2012.691364
关键词
p53 protein; molecular dynamics; conformational flexibility; DNA binding domain (DBD); binding site
资金
- Ministry of Science and Education of the Russian Federation [P857, P721, 14.740.11.0001]
- Presidium of the Russian Academy of Sciences [B.26.29, A.II.6]
- Russian Academy of Science [29, 19]
- Russian Foundation for Basic Research [11-04-92712-IND, 11-04-01221-a, 11-04-01771]
- EU-FP7 SYSPATHO project [260429]
- Department of Science and Technology, Govt. of India
- Russian Academy of Sciences, Russia
Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn2+ is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn2+-binding pocket can presumably exert an influence on Zn2+ position in the Zn2+-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 Zn2+ 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-Zn2+ complexes was used to detect significant deviations in conformation of the mutant p53 forms. MD simulations demonstrated that (1) the two substitutions in the Zn2+-binding pocket caused changes in the conformation of the p53 DNA-binding motif, as compared with the wild-type (WT) p53; (2) binding of Zn2+ to the p53 mutant forms reduced the effect of the substitutions on conformational change; and (3) Zn2+ binding in the normal position compensated the effect of the mutations on the conformation in comparison to the altered Zn2+ position.
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