Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism

Nature. 2006 Oct 19;443(7113):870-4. doi: 10.1038/nature05143. Epub 2006 Oct 11.


Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism
  • Crystallography, X-Ray
  • Glucagon / chemistry
  • Glucagon / metabolism
  • Humans
  • Insulin / chemistry*
  • Insulin / metabolism*
  • Insulysin / chemistry*
  • Insulysin / metabolism*
  • Islet Amyloid Polypeptide
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Substrate Specificity


  • Amyloid
  • Amyloid beta-Peptides
  • Insulin
  • Islet Amyloid Polypeptide
  • Glucagon
  • Insulysin

Associated data

  • PDB/2G47
  • PDB/2G48
  • PDB/2G49
  • PDB/2G54
  • PDB/2G56