Within the a typical human cell, approximately 2 yards of DN A is stuffed into a spherical space only 0.00025 inches in diameter. This enormous compaction leads to tangles and knots in the D NA that can kill the cell when it tries to divide. In order to alleviate this topological dilemma, cells have evolved specialized enzymes known as topoisomerases. These molecular machines untangle and unknot D NA by cutting one DNA duplex in half, passing a second D N A duplex through the gap, and resealing the break. The picture you see is a three-dimensional reconstruction of a topoisomerase determined using data from X-ray crystallographic studies (blue, red, and yellow regions); from these data researchers can pinpoint the location of nearly every atom in the protein. The topoisomerase is modeled in the process of gripping a broken D NA duplex (shown in green) and transporting a second duplex (the multicolored rosette). This is part of the work carried out in the laboratory of James Berger in the Department of Molecular and Cell Biology.

Once thought to be mere laboratory curiosities, topoisomerases are now known to be essential for the livelihood of all organisms, from viruses and bacteria to humans. Moreover, it is now known that topoisomerases are targets for a large number of clinically used drugs, including anticancer agents and antibiotics. These drugs block the enzyme after it has cleaved the D N A, causing lethal breaks in the organism's chromosome. Understanding the molecular mechanisms behind the drug's action remains an important research goal, one in which the power of X-ray crystallography will play a critical role to resolve drug/topoisomerase interactions at atomic resolution.