The structure of an enzyme that degrades insulin and amyloid-beta suggests a possible way to design drugs that combat the abnormal levels of these proteins in sufferers of diabetes or Alzheimer's disease.
Insulin-degrading enzyme (IDE) is unusual because it binds and cleaves diverse substrates. In research to be published online by Nature, Wei-Jen Tang and his colleagues determine the structure of the enzyme in complex with four substrates, including a subunit of insulin or amyloid. They show that the enzyme undergoes a conformational change when it binds its substrate such that the two ends form an enclosed chamber shaped like a triangular prism. Small proteins that do not have significant positive charges at a certain end make better substrates.
Mutations that disrupt the interaction of the two ends of IDE promote the opening of the chamber to substrates and increase the rate of substrate breakdown 40-fold; hence, drugs similarly designed to disrupt the shape of IDE might help clear the accumulation of amyloid-beta that is characteristic of Alzheimer's disease.
Wei-Jen Tang (University of Chicago, IL, USA)
Dennis Selkoe (Harvard Medical School, Boston, MA, USA)
Abstract available online.
(C) Nature press release.
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