Protein Name

insulin-degrading enzyme in complex with insulin B chain


Homo sapiens (human)

Biological Context

Insulin-degrading enzyme (IDE), a Zn2+ metalloprotease, degrades insulin and amyloid-β. It also degrades amylin and glucagon so that IDE is one of the rare enzymes degrading a wide range of substrate with high affinity.
Insulin is an essential molecule for regulating glucose metabolism and the lack of insulin activity causes high blood sugar levels and diabetes. It seems that cerebral accumulation of amyloid-β would be a factor of Alzheimer disease. IDE is important for glucose and amyloid-β regulation and loss-of-function mutations in IDE cause glucose intolerance and amyloid-β accumulation in brain. On the other hand enhanced IDE activity effectively reduces cerebral amyloid-β. Thus, the design of new IDE-based therapies is expected to correct high blood sugar concentration and brain amyloid-β accumulation.

Structure Description


Crystal structure of Zn2+ bound, catalytically inactive IDE mutant IDE-E111Q in complex with insulin B chain has been solved at 2.25Å resolution. IDE consists of four structurally homologous domains. Domain 1 and 2 are in the N-terminal part (IDE-N) and Domain 3 and 4 in the C-terminal part (IDE-C). The IDE structure described is the closed form, which captures insulin B chain in a triangular prism-like chamber.

The IDE domain 1 contains the catalytic cleft with Zn2+. At this site, the insulin B chain, which is one of the possible substrates, does a conformational change from the native structure to form β strands on its N terminus and catalytic sites. It then attaches to the IDE by forming β sheets. In this structure, the remaining regions are disordered (Fig. 1).

Contributing factors for substrate recognition by IDE were revealed. Favorable binding of the substrate N terminus and cleavage sites are crucial. In addition, charge distribution in the C terminus is also important. The surface of the IDE-C chamber is positively charged so that substrates without positive charges in their C terminus are suitable. Another factor is size, because the catalytic chamber of IDE can accommodate only relatively small peptides. Insulin fits these conditions. In addition, amyloid-β, amylin, and glucagon are also acceptable as IDE substrates and their complex structures have been solved (xPSSS:2G47, xPSSS:2G48, and xPSSS:2G49 respectively). These substrates also form β strands to contact IDE, which is consistent with insulin B chain.

Although it seems that IDE changes allosterically its open-closed conformation, details including key small molecules remain unknown.

IDE-bound IDE-free
(Fig. 1-a) native structure of insulin B chain.
IDE binding regions (orange and red) are
part of an α helix in the native structure.
(Fig. 1-b) IDE-bound form of insulin B chain.
N terminus (orange)
and IDE catalytic segment (red) in insulin B chain
which are binding regions to IDE.
Dotted lines show disordered region.

IDE domain 1 (green), 2 (blue), 3 (yellow), and 4 (pink).
The sphere represents the zink ion.

(Fig. 1) Conformational change of the insulin B chain.

Protein Data Bank (PDB)



Shen, Y. Joachimiak, A. Rosner, M.R. Tang, W.-J.; "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism"; Nature; (2006) 443:870-874.


author: Naoya Fujita

Japanese version:PDB:2G54