PDBsum entry 3e4z

Hydrolase/hormone

PDB id: 3e4z

Contents

Protein chain

953 a.a. *

Ligands

ALA-TYR-ARG ×2

LEU-VAL-ASP-THR-LEU-GLN ×2

Metals

_ZN ×2

Waters ×724

* Residue conservation analysis

PDB id:

3e4z

Name:

Hydrolase/hormone

Title:

Crystal structure of human insulin degrading enzyme in complex with insulin-like growth factor ii

Structure:

Insulin-degrading enzyme. Chain: a, b. Fragment: unp residues 42-1019. Synonym: insulin protease,insulinase,insulysin. Engineered: yes. Mutation: yes. Insulin-like growth factor ii. Chain: c, d. Fragment: unp residues 25-91.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: bl21(de3)pubs520. Gene: ide. Expressed in: escherichia coli. Gene: igf2. Expressed in: escherichia coli

Resolution:

2.28Å R-factor: 0.197 R-free: 0.230

Authors:

Q.Guo,M.Manolopoulou,W.-J.Tang

Key ref:

Q.Guo et al. (2010). Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme. J Mol Biol, 395, 430-443. PubMed id: 19896952

Date:

12-Aug-08 Release date: 18-Aug-09

Protein chains

P14735  (IDE_HUMAN) -  Insulin-degrading enzyme from Homo sapiens

Seq: 1019 a.a.

Struc: 953 a.a.*

* PDB and UniProt seqs differ at 13 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.24.56 - insulysin.
• Reaction: Degradation of insulin, glucagon and other polypeptides. No action on proteins.
• Cofactor: Zn(2+)

J Mol Biol 395:430-443 (2010)

PubMed id: 19896952

Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme.

Q.Guo, M.Manolopoulou, Y.Bian, A.B.Schilling, W.J.Tang.

ABSTRACT

Insulin-degrading enzyme (IDE) is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid-beta, peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulin-like growth factor (IGF)-II and transforming growth factor-alpha (TGF-alpha) over IGF-I and epidermal growth factor, respectively. Here, we used high-accuracy mass spectrometry to identify the cleavage sites of human IGF-II, TGF-alpha, amylin, reduced amylin, and amyloid-beta by human IDE. We also determined the structures of human IDE-IGF-II and IDE-TGF-alpha at 2.3 A and IDE-amylin at 2.9 A. We found that IDE cleaves its substrates at multiple sites in a biased stochastic manner. Furthermore, the presence of a disulfide bond in amylin allows IDE to cut at an additional site in the middle of the peptide (amino acids 18-19). Our amylin-bound IDE structure offers insight into how the structural constraint from a disulfide bond in amylin can alter IDE cleavage sites. Together with NMR structures of amylin and the IGF and epidermal growth factor families, our work also reveals the structural basis of how the high dipole moment of substrates complements the charge distribution of the IDE catalytic chamber for the substrate selectivity. In addition, we show how the ability of substrates to properly anchor their N-terminus to the exosite of IDE and undergo a conformational switch upon binding to the catalytic chamber of IDE can also contribute to the selective degradation of structurally related growth factors.