PDBsum entry 2wk3

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Hydrolase PDB id
Protein chains
958 a.a. *
_ZN ×2
Waters ×234
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-42)
Structure: Insulin degrading enzyme. Chain: a, b. Synonym: insulin protease, insulysin, insulinase. Engineered: yes. Mutation: yes. Beta-amyloid protein 42. Chain: c, d. Fragment: beta-amyloid protein 42, residues 672-713. Synonym: beta-app42, amyloid beta a4 protein synonym:
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expressed in: escherichia coli bl21(de3).
2.59Å     R-factor:   0.189     R-free:   0.232
Authors: Q.Guo,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
05-Jun-09     Release date:   03-Nov-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P14735  (IDE_HUMAN) -  Insulin-degrading enzyme
1019 a.a.
958 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 13 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Insulysin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Degradation of insulin, glucagon and other polypeptides. No action on proteins.
      Cofactor: Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   13 terms 
  Biological process     metabolic process   18 terms 
  Biochemical function     catalytic activity     20 terms  


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.
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.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21274957 G.Grasso, A.Pietropaolo, G.Spoto, G.Pappalardo, G.R.Tundo, C.Ciaccio, M.Coletta, and E.Rizzarelli (2011).
Copper(I) and Copper(II) Inhibit Aβ Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer's Disease.
  Chemistry, 17, 2752-2762.  
20959807 M.Ren, Q.Guo, L.Guo, M.Lenz, F.Qian, R.R.Koenen, H.Xu, A.B.Schilling, C.Weber, R.D.Ye, A.R.Dinner, and W.J.Tang (2010).
Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme.
  EMBO J, 29, 3952-3966.
PDB codes: 2x69 2x6g 2x6l
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