2IOM

Mouse p53 core domain soaked with 2-propanol

2IOM の概要

• エントリーDOI: 10.2210/pdb2iom/pdb
• 関連するPDBエントリー: 2IOI 2IOO
• 分子名称: Cellular tumor antigen p53, ZINC ION, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• 機能のキーワード: ig fold, transcription, antitumor protein
• 由来する生物種: Mus musculus (house mouse)
• 細胞内の位置: Cytoplasm : P02340
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23061.70

構造登録者

Ho, W.C.,Luo, C.,Zhao, K.,Chai, X.,Fitzgerald, M.X.,Marmorstein, R. (登録日: 2006-10-10, 公開日: 2006-12-05, 最終更新日: 2024-02-21)

主引用文献

Ho, W.C.,Luo, C.,Zhao, K.,Chai, X.,Fitzgerald, M.X.,Marmorstein, R.
High-resolution structure of the p53 core domain: implications for binding small-molecule stabilizing compounds.
ACTA CRYSTALLOGR.,SECT.D, 62:1484-1493, 2006

PubMed Abstract: 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.

PubMed: 17139084
DOI: 10.1107/S090744490603890X

実験手法

X-RAY DIFFRACTION (2 Å)