Structural Basis for the Pharmacological Rescue of Mutant p53 with Small Molecule Compounds
Abstract
The p53 protein is a tumor suppressor crucial to maintaining genomic integrity. In the event of DNA damage, p53 is responsible for transcribing genes leading to cell death. A class of mutations which occur in the core domain (102-292) leads to thermodynamic destabilization and inability to bind its cognate DNA sequence. Small molecules which bind to and stabilize mutant p53 core domain have potential to be therapeutically useful. Two potential "hot spots" on the surface of the mouse p53 core domain have been discovered which can be targeted by small molecule compounds. One hot spot was discovered by soaking the crystal lattice with various organic solvents and locating the solvents in the electron density. Another potential hot spot was located in the high resolution structure of the mouse core domain where a molecule of tris(hydroxymethyl)aminomethane (Tris) was observed to bind on the surface of the protein, making numerous hydrogen bonding contacts. Urea denaturation experiments show an increase in stability (^.37kcalcal/mol) in the presence of 1mM Tris when compared to protein in the absence of Tris. Although the gain in stability is relatively modest, the structural data acquired in this study can guide the way to designing compounds with increased activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA436949
Entities
People
- William C. Ho
Organizations
- University of Pennsylvania