CRYSTAL-STRUCTURE OF A P53 TUMOR-SUPPRESSOR DNA COMPLEX - UNDERSTANDING TUMORIGENIC MUTATIONS

Mutations in the p53 tumor suppressor are the most frequently observed genetic alterations in human cancer. The majority of the mutations oc cur in the core domain which contains the sequence-specific DNA bindin g activity of the p53 protein (residues 102-292), and they result in l oss of DNA binding. The crystal structure of a complex containing the core domain of human p53 and a DNA binding site has been determined at 2.2 angstroms resolution and refined to a crystallographic R factor o f 20.5 percent. The core domain structure consists of a beta sandwich that serves as a scaffold for two large loops and a loop-sheet-helix m otif. The two loops, which are held together in part by a tetrahedrall y coordinated zinc atom, and the loop-sheet-helix motif form the DNA b inding surface of p53. Residues from the loop-sheet-helix motif intera ct in the major groove of the DNA, while an arginine from one of the t wo large loops interacts in the minor groove. The loops and the loop-s heet-helix motif consist of the conserved regions of the core domain a nd contain the majority of the p53 mutations identified in tumors. The structure supports the hypothesis that DNA binding is critical for th e biological activity of p53, and provides a framework for understandi ng how mutations inactivate it.