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Context

Insulin degrading enzyme (or IDE), is a human metallopeptidase. It plays an important role in the cellular degradation of many molecules. Its activity was first related only to insulin, but now, we know that IDE interacts with insulin, glugacon and bradykinin.

The surprising thing is that IDE can be in complex with bradykinin. In fact, bradykinin is a small peptide (9 amino acids), and generally, IDE has substrates longer than 20 amino acids.

Normally, IDE can not bind small molecules. That's why this complex is interessant to study. Bradykinin is a small ligand and can also interacts with the catalytic chamber of IDE.

The IDE-bradykinin complex has a complexity in the substrate binding and recognition mechanism of IDE.

Previous studies (???) reveal that IDE uses an exosite to interact with the N-terminal end of its substrate (???), away from the catalytic site. This particular catch allows multiple cleavages of substrates by IDE. It was also observed that the binding of bradykinin occurs at the exosite and not the catalytic site.

Insuline degrading enzyme (IDE)

IDE (EC 3.4.24.56) is a human enzyme of the metallopeptidase family, not well-known yet. It is composed by more than 1000 residues and has a huge catalytic cavity. It is made of 2 parts linked by a loop, and it switches between an open and a close state. The size of its catalytic chamber allows the binding of peptides (70 amino acids long). IDE hydrolyzes a lot of substrates which have many differents biological activities. Its substrate can be insuline, glucagon, amyline or bradykinin.

Exosite: an essential element for the catalysis

Catalytic mechanism

Bradykinin

Bradykinin is a short nonapeptide of the family of kinins. It's in response to an inflammatory envent and serves as a mediator of pain, inflammation and vasodilatation. Today, we know that kinins can be degraded by IDE.

We supposed that IDE may bind two molecules of bradykinin at the same time

Interactions between bradykinin and IDE

Hypothetical role of bradykinin on IDE

Today, we can supposed that binding of bradykinin at the exosite stimulated the conformationnal change of IDE, from its open to its close state. We can also suggests that IDE binds 2 bradykinin thanks to their small lenght.

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