Researchers from the University of Chicago and Argonne National Laboratory have deciphered the three-dimensional structure of insulin-degrading enzyme, a promising target for new drugs because it breaks down not only insulin but also the amyloid-beta protein, which has been linked to the cognitive decline of Alzheimer's disease.

In the October 19, 2006, issue of Nature (available online Oct. 11), the researchers describe the structures of insulin-degrading enzyme (IDE) in complex with four of the proteins it digests: insulin, amyloid-beta, amylin and glucagon. The structures are exciting because they suggest ways to develop drugs that could either speed up or slow down this ubiquitous enzyme's activity.

"The structure of insulin-degrading enzyme tells us a lot about how it works, which is somewhat unorthodox," said Wei-Jen Tang, Ph.D., associate professor in the Ben May Institute for Cancer Research at the University of Chicago and director of the study. "Understanding how it works gives us clues about how to design drugs either to inhibit or activate it."

"By introducing small, targeted mutations, we have already been able to increase the enzyme's activity by as much as 40-fold," he said. "That gives us a blueprint for the next step, trying to devise a drug that would produce a similar effect."

Ever since I. Arthur Mirsky discovered IDE in 1949, physicians have sought ways to manipulate it. Mirsky thought that by inhibiting the enzyme he could help diabetics by making their insulin remain active longer. More recently, as scientists realized that IDE was also involved in clearance of amyloid-beta, they have begun searching for ways to supercharge the enzyme to see if it could prevent the build-up of the amyloid plaques that are a hallmark of Alzheimer's disease.

Despite more than half a century of intensive research, however, insulin-degrading enzyme has remained "an especially elusive pharmacological targe
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Contact: John Easton
John.Easton@uchospitals.edu
773-702-6241
University of Chicago Medical Center
11-Oct-2006