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‣ Structural and functional implications of p53 missense cancer mutations

Tan, Yuhong; Luo, Ray
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 26/06/2009 Português
Relevância na Pesquisa
Most human cancers contain mutations in the transcription factor p53 and majority of these are missense and located in the DNA binding core domain. In this study, the stabilities of all core domain missense mutations are predicted and are used to infer their likely inactivation mechanisms. Overall, 47.0% non-PRO/GLY mutants are stable (ΔΔG < 1.0 kT) and 36.3% mutants are unstable (ΔΔG > 3.0 kT), 12.2% mutants are with 1.0 kT < ΔΔG < 3.0 kT. Only 4.5% mutants are with no conclusive predictions. Certain types of either stable or unstable mutations are found not to depend on their local structures. Y, I, C, V, F and W (W, R and F) are the most common residues before (after) mutation in unstable mutants. Q, N, K, D, A, S and T (I, T, L and V) are the most common residues before (after) mutation in stable mutants. The stability correlations with sequence, structure, and molecular contacts are also analyzed. No direct correlation between secondary structure and stability is apparent, but a strong correlation between solvent exposure and stability is noticeable. Our correlation analysis shows that loss of protein-protein contacts may be an alternative cause for p53 inactivation. Correlation with clinical data shows that loss of stability and loss of DNA contacts are the two main inactivation mechanisms. Finally...