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Structure of enzyme offers treatment clues for diabetes, Alzheimer's

t," biochemist Malcolm Leissring of the Scripps Research Institute and neurobiologist Dennis Selkoe of Harvard Medical School wrote in a commentary that accompanies the Nature article.

Using the Advanced Photon Source at Argonne National Laboratory, Tang and colleagues were able to solve the structures of this enzyme in complex with insulin and with amyoid-beta, as well as amylin and glucagon. These "high-resolution crystal structures open the door to the rational design of pharmacological modulators of this important protease," wrote Leissring and Selkoe.

The enzyme, Tang's team reports, resembles the video-game character "Pac-Man," with two bowl-shaped halves joined by a hinge at one end and held closed, most of the time, by a latch of hydrogen bonds on the other end. When the bowls come together, like a shut mouth, they enclose a chamber, shaped like a triangular prism, with a base that measures 35 x 34 x 30 angstroms and a height of 36 angstroms, large enough to contain relatively small peptides, such as insulin or amyloid-beta, which have fewer than 50 amino acids.

Although it can cleave larger molecules, the proteins IDE degrades most readily fit neatly within this chamber. Negative electrical charges on their outer surfaces help to align them with the positive charges on one inner surface of the chamber. Once they are in place, the enzyme slices them multiple times into tiny pieces, which are then discarded.

Although the enzyme's structure is similar to Pac-Man, its behavior differs. Pac-Man keeps his mouth wide open to gobble up anything in his path. With IDE the mouth is usually closed. The hydrogen-bond latch that holds the jaws together protects its active, or catalytic site.

But in a series of experiments, Tang and colleagues were able to make small mutations of IDE that altered only the latch, disrupting the alignment of contacts that normally keep the enzyme closed. Three of these altered ver
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Contact: John Easton
John.Easton@uchospitals.edu
773-702-6241
University of Chicago Medical Center
11-Oct-2006


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