Crystal
structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic
mutations.
Cho Y, Gorina S, Jeffrey PD, Pavletich NP
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering
Cancer Center, New York, NY 10021.
Mutations in the p53 tumor suppressor are the most frequently
observed genetic alterations in human cancer. The majority of the
mutations occur in the core domain which contains the sequence-specific
DNA binding activity of the p53 protein (residues 102-292), and they
result in loss 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 of 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 motif. The two loops, which are held together in
part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix
motif form the DNA binding surface of p53. Residues from the loop-sheet-helix
motif interact in the major groove of the DNA, while an arginine from
one of the two large loops interacts in the minor groove. The loops
and the loop-sheet-helix motif consist of the conserved regions of
the core domain and contain the majority of the p53 mutations identified
in tumors. The structure supports the hypothesis that DNA binding
is critical for the biological activity of p53, and provides a framework
for understanding how mutations inactivate it.
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