Nature Structural Biology pp 756 - 760

The human protein p53 regulates the response to DNA damage by binding specific regions of DNA and activating transcription of genes involved in the cell cycle and in cell death. It is also often found in a mutated, inactive form in tumor cells, and is thought to play a key role in the development of many cancers. Understanding how the activity of p53 is controlled may be an important step toward developing cancer treatments involving the conversion of the inactive form found in tumors to the active form.

The C-terminal region of p53 is thought to control the activity of the protein, as this region inhibits specific binding of p53 to DNA and must be modified or removed to allow full transcriptional activity. Exactly how this works, however, is unclear. A popular hypothesis has been that binding of the unmodified C-terminal region to other parts of the protein causes a structural change that is incompatible with specific DNA binding. However, as reported in the September issue of Nature Structural Biology by Arrowsmith and coworkers at the University of Toronto, this hypothesis appears to be incorrect. Using nuclear magnetic resonance (NMR), these authors show that the inactive and active forms of p53, with and without the C-terminal region, have the same structure. Surprisingly, the C-terminal region does not appear to interact with other parts of the protein or induce structural changes. Researchers interested in activating the p53 found in tumor cells may now have to reevaluate and investigate further the natural regulation mechanisms of this protein.

Drs. Ahn and Prives further discuss the background and implications of this study in a related News and Views article.

Nature Structural Biology pp 779 - 783

In 1976, 152 people contracted a severe respiratory disease while attending an American Legion convention in Philadelphia; 22 of the patients died. The culprit of this disease - called the Legionnaires' disease because of the outbreak at the convention - is a rod-shaped bacterium called Legionella pneumophila. The bacteria live in warm stagnant water sources, such as in air conditioning cooling towers, shower heads or humidifiers, and are transmitted to humans through inhaling the water droplets generated by these devices. Because ~70% of the cases of the Legionnaires' disease are in epidemic form, both prevention and development of treatment against the disease are important tasks.

At the early stage of L. pneumophila infection, the bacteria multiply inside human lung cells. This capability is enhanced by a bacterial protein called macrophage infectivity potentiator protein (Mip). Mip has an enzyme activity that speeds up the protein folding reaction, although it is not yet known if this activity is involved in L. pneumophila infection. To begin to understand the role of Mip in L. pneumophila infection, Hilgenfeld and coworkers at the Institute of Molecular Biotechnology, Germany, have determined the crystal structure of Mip.

The molecular architecture of Mip is a V-shaped dimer. At the diverging ends of the V are two domains that can bind FK506, a compound that inhibits the enzyme activity of Mip. By also determining the structure of Mip in complex with FK506, the authors have provided details of how this compound binds to the protein. Because FK506 is an immunsuppressant, it is not an appropriate drug for treating L. pneumophila infection. Nonetheless, these results represent a starting point from which rational searches for host cell protein(s) that interact with Mip, as well as drugs that specifically target Mip, can be initiated.