2ioo

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Revision as of 18:44, 29 January 2008

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spinqualitylabelsall models 2ioo, resolution 2.02Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the mouse p53 core domain

Overview

The p53 transcriptional regulator is the most frequently mutated protein, in human cancers and the majority of tumor-derived p53 mutations map to, the central DNA-binding core domain, with a subset of these mutations, resulting in reduced p53 stability. Here, the 1.55 A crystal structure of, the mouse p53 core domain with a molecule of, tris(hydroxymethyl)aminomethane (Tris) bound through multiple hydrogen, bonds to a region of p53 shown to be important for repair of a subset of, tumor-derived p53-stability mutations is reported. Consistent with the, hypothesis that Tris binding stabilizes the p53 core domain, equilibrium, denaturation experiments are presented that demonstrate that Tris binding, increases the thermodynamic stability of the mouse p53 core domain by 3.1, kJ mol(-1) and molecular-dynamic simulations are presented revealing an, overall reduction in root-mean-square deviations of the core domain of 0.7, A when Tris is bound. It is also shown that these crystals of the p53 core, domain are suitable for the multiple-solvent crystal structure approach to, identify other potential binding sites for possible core-domain, stabilization compounds. Analysis of the residue-specific temperature, factors of the high-resolution core-domain structure, coupled with a, comparison with other core-domain structures, also reveals that the L1, H1-S5 and S7-S8 core-domain loops, also shown to mediate various p53, activities, harbor inherent flexibility, suggesting that these regions, might be targets for other p53-stabilizing compounds. Together, these, studies provide a molecular scaffold for the structure-based design of, p53-stabilization compounds for development as possible therapeutic, agents.

About this Structure

2IOO is a Single protein structure of sequence from Mus musculus with as ligand. Full crystallographic information is available from OCA.

Reference

High-resolution structure of the p53 core domain: implications for binding small-molecule stabilizing compounds., Ho WC, Luo C, Zhao K, Chai X, Fitzgerald MX, Marmorstein R, Acta Crystallogr D Biol Crystallogr. 2006 Dec;62(Pt 12):1484-93. Epub 2006, Nov 23. PMID:17139084

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