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Karolin Luger
Many factors have come together to produce the current crop of new findings in structural biology. "All operations are faster," says Douglas C. Rees, an HHMI investigator at the California Institute of Technology. "It's also easier to decipher structures on the basis of data, thanks to computational programs developed by Axel Brunger [an HHMI investigator at Stanford University] and others."
In addition, all research on structures has benefited greatly from recent progress in genomics. "Now, when we're interested in understanding a particular mechanism, we can pull out the proteins that carry out that function from many different genomes," says Kuriyan. "Sometimes the genes from one organism produce proteins that for some reason are more stable and crystallize better than the human or other genes that you were working on originally."
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Solving the structure of the nucleosome—a fundamental chromatin component made up of a disk of proteins surrounded by DNA—was a starting point for Karolin Luger. Since that achievement, she has shifted her focus from what the nucleosome is to what it does, and how the structure changes as it interacts with other molecules. In this side view of the nucleosome core particle, DNA is depicted as a light blue surface; atoms of the histone octamer are represented as spheres.
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Photo Illustration: Karolin Luger
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Scientists are also learning how large and shifting molecular machines can be caught in the act and crystallized as a whole. "Some of it is just luck," says Kuriyan. "But some of it is the result of doing experiments that tease out how the molecules work at a biochemical level. It's like photographing a tiger at the water's edge. You need to understand that the tiger comes to the water, know when it comes to water, position yourself by the pool—finally you get that moment when everything is right, and you snap it."
As these methods improve, researchers will have more opportunities to see for themselves "how a structure talks to you," as Nobel prize winner Roderick MacKinnon, an HHMI investigator at the Rockefeller University, once described the value of structural biology. Eventually this work will lead to a better understanding of how living cells function and how to repair them when they fail. 
Photo: Paul Fetters
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