p53 - a Tumor Suppressor Protein

Mutations in the p53 tumor suppressor protein are the most commonly observed genetic alterations in human cancer. About half of all cancers involve mutations of p53 that inactivate this protein, and many other cancers involve cellular or viral oncogenes that inactivate the normal p53 protein. Nikola Pavletich and his coworkers have described the crystal structure of a complex of the core domain of p53 and DNA.

The crystals studied by Pavletich contain one DNA duplex and three p53 core domain proteins. Only one of the proteins in this complex binds to a consensus DNA sequence in the middle of the DNA duplex.

A single Zn ion is coordinated by the protein, just a few Angstroms from the DNA backbone.

The structure of the core domain is built around an antiparallel beta sheet of four strands and another antiparallel beta sheet of five strands that together form a beta sandwich.

Near the DNA duplex there is a loop-sheet-helix motif that packs tightly against one end of the beta sandwich.

Two loops and a short helix surround and coordinate the zinc ion. More specifically, the zinc ion is tetrahedrally coordinated by three cysteines and a histidine.

This button provides a 360 degree tour of the p53-DNA complex. Pay special attention to the coordination of the zinc ion and the interaction of the purple helix of p53 with the DNA.

Taking a closer look at the core domain, it is possible to examine the "mutation hot-spots" on p53. The residues most frequently mutated in cancer are all at or near the protein-DNA interface, whereas the residues that are not mutated, or are mutated least frequently, are typically far from the DNA. The mutation hot spots (and the frequency with which they are mutated in tumors) are:

Arg-175 (6.1%)

Gly-245 (6.0%)

Arg-248 (9.6%)

Arg-249 (5.6%)

Arg-273 (8.8%)

Arg-282 (4.0%)

Use the following button to "rock" the structure back and forth around the y-axis.

This will provide a better three-dimensional perspective on the "hot spots" you have just highlighted.

You may wish to manipulate this image yourself:

  • Click and hold the left mouse button to rotate the image about the x and y axes.
  • Rotate about the z axis by pressing the shift key and right mouse button together.
  • The image may be translated along the x and y axes by pressing control and the right mouse button.
  • By pressing shift and the left mouse button together, you may zoom the image in or out.
  • Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.