High-resolution structure of the p53 core domain: implications for binding small-molecule stabilizing compounds

Area of Science:

• Structural Biology
• Molecular Biophysics
• Cancer Therapeutics

Background:

• The p53 protein is a critical transcriptional regulator frequently mutated in human cancers.
• Many tumor-derived p53 mutations occur in the DNA-binding core domain, often reducing protein stability.
• Stabilizing the p53 core domain is a potential therapeutic strategy for cancer.

Purpose of the Study:

• To determine the crystal structure of the mouse p53 core domain bound to tris(hydroxymethyl)aminomethane (Tris).
• To investigate the stabilizing effect of Tris on the p53 core domain.
• To identify potential targets for developing p53-stabilizing compounds.

Main Methods:

• 1.55 Å crystal structure determination of the mouse p53 core domain with Tris.
• Equilibrium denaturation experiments to assess thermodynamic stability.
• Molecular-dynamic simulations to analyze structural changes upon Tris binding.
• Analysis of residue-specific temperature factors and comparison with other structures.

Main Results:

• Tris binds to a critical region of the p53 core domain via multiple hydrogen bonds.
• Tris binding increases the thermodynamic stability of the mouse p53 core domain by 3.1 kJ mol⁻¹.
• Molecular-dynamic simulations show a reduction in root-mean-square deviations, indicating increased stability.
• Flexible regions (L1, H1-S5, S7-S8 loops) within the p53 core domain are identified as potential targets for stabilization.

Conclusions:

• Tris binding effectively stabilizes the p53 core domain, offering a molecular basis for therapeutic intervention.
• The study provides a structural scaffold for the rational design of novel p53-stabilizing compounds.
• These findings pave the way for developing new therapeutic agents targeting p53 stabilization in cancer.