Luger made this discovery while analyzing the shape of a nucleosome, the basic repeating unit of chromatin, to which a fragment of the Kaposi virus was attached.

"The structure shows that the nucleosome can act as a docking platform for a virus," she says. "This is a new role for it—and potentially this interaction could be prevented with antiviral drugs."

Now she hopes to tackle a much bigger problem: discovering the shape of chromatin itself. "Our genetic information, which is stored in DNA, is not read linearly but packed into these highly convoluted and organized structures, and a lot of cancer comes from the wrong readout of genes," she says. "To discover how this happens, we need to understand the structures involved."

Luger's goal illustrates a new trend in structural biology: focusing on the shapes of ever more intricate "molecular machines," groups of molecules that self-assemble to do key jobs in living cells. Until about 15 years ago, scientists were happy to determine the structure of a single protein at resolution high enough so they could see the position of each of its atoms. Then, spurred by more efficient methods of growing crystals, better computers, and the more intense x-rays produced by a new generation of synchrotrons, they began to solve the atomic structures of single proteins bound to single receptors. Now they want more. They want to see the 3-D structures of the powerful molecular machines that produce our proteins, repair our DNA, defend us against microbes and, in effect, control our health.

Today's structural biologists want to see the 3-D structures of the powerful molecular machines that, in effect, control our health.

These complex functional units consist of perhaps five to a dozen different proteins or nucleic acids that have come together for specific purposes. At times several different molecular machines unite to form even larger functional units.

"We're now able to visualize molecular assemblies of such complexity that I would never have predicted they could be crystallized," says John Kuriyan, an HHMI investigator at the University of California, Berkeley. Kuriyan's lab recently solved the intricate structure of a "clamp loader assembly," a cluster of proteins that positions the machines that replicate DNA. It is difficult enough to grow a well-ordered crystal—the essential first step in x-ray crystallography—when dealing with just one or two components, he points out (see sidebar, "First, Grow a Crystal"). But, in 2000, Thomas A. Steitz, an HHMI investigator at Yale University, Peter B. Moore of Yale, and their colleagues solved the atomic structure of a complicated molecular machine—the large subunit of the ribosome, the cell's protein-building factory—at high resolution. This relatively enormous machine contained 3,000 nucleotides of RNA as well as 31 different proteins.

"When I first heard Steitz describe this work... I felt much as I did when humans first stepped on the moon," Kuriyan recalls. It was the largest molecular-machine structure that had ever been solved in such detail. Around the same time, the smaller subunit of the ribosome was also visualized, and this year the total ribosome structure—which shows how the ribosome produces new chains of protein, one amino acid at a time—was solved at reasonably high resolution.

The conquest of the large ribosome subunit emboldened scientists to tackle other molecular machines that in the past had seemed forbiddingly large. Their efforts have had some early and potentially useful results, such as leading biologists to learn exactly how certain classes of antibiotics kill bacteria and why certain bacteria are resistant to drugs. In order to prevent bacteria from producing new proteins, drugs actually target the bacteria's ribosomes. Recent studies in Steitz's lab and elsewhere have identified the specific crevices of bacterial ribosomes into which particular antibiotics fit. This discovery could lead to drugs that fit more tightly, are more effective at low doses, and have fewer side effects.

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