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Hydrolase PDB id
2g48
Jmol
Contents
Protein chains
968 a.a. *
18 a.a. *
17 a.a. *
Ligands
DIO ×2
Waters ×696
* Residue conservation analysis
PDB id:
2g48
Name: Hydrolase
Title: Crystal structure of human insulin-degrading enzyme in complex with amylin
Structure: Insulin-degrading enzyme. Chain: a, b. Synonym: insulysin, insulinase, insulin protease. Engineered: yes. Mutation: yes. Islet amyloid polypeptide. Chain: c, d. Fragment: residues 34-70. Synonym: diabetes-associated peptide, dap, amylin,
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ide. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence occurs naturally in homo sapiens (humans)
Biol. unit: Dimer (from PQS)
Resolution:
2.60Å     R-factor:   0.196     R-free:   0.225
Authors: Y.Shen,W.-J.Tang
Key ref:
Y.Shen et al. (2006). Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature, 443, 870-874. PubMed id: 17051221 DOI: 10.1038/nature05143
Date:
21-Feb-06     Release date:   24-Oct-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P14735  (IDE_HUMAN) -  Insulin-degrading enzyme
Seq:
Struc: 		 
Seq:
Struc: 		1019 a.a.
968 a.a.*
Protein chain
Pfam   ArchSchema ?
P10997  (IAPP_HUMAN) -  Islet amyloid polypeptide
Seq:
Struc: 		89 a.a.
18 a.a.
Protein chain
Pfam   ArchSchema ?
P10997  (IAPP_HUMAN) -  Islet amyloid polypeptide
Seq:
Struc: 		89 a.a.
17 a.a.
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.3.4.24.56  - Insulysin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Degradation of insulin, glucagon and other polypeptides. No action on proteins.
      Cofactor: Zinc
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   12 terms 
  Biological process     interspecies interaction between organisms   13 terms 
  Biochemical function     catalytic activity     18 terms  

 

 
DOI no: 10.1038/nature05143 Nature 443:870-874 (2006)
PubMed id: 17051221  
 
 
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
Y.Shen, A.Joachimiak, M.R.Rosner, W.J.Tang.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: Overall structure of IDE-E111Q in complex with insulin B chain. a, Secondary structure representation of the IDE-E111Q–insulin B chain complex. Domains 1, 2, 3 and 4 are coloured green, blue, yellow and red, respectively. Zn^2+ and insulin B chain are coloured magenta and orange, respectively. b, Structure homology of the four domains of IDE. c, Surface representation of the substrate-binding chamber of IDE. The outer surface of IDE and the substrate chamber are coloured pale yellow and brown, respectively. d, Electrostatic surface representation of the IDE substrate-binding chamber. The inner substrate binding chambers of IDE-N and IDE-C are marked by triangles. The surface is coloured as follows: negative, red; positive, blue; neutral, white. e, Catalytic centre of IDE. The simulated annealing omit map (magenta) is contoured at 3.5 . IDE and insulin B chain are coloured cyan and orange, respectively. 		Figure 4.
Figure 4: Conformational changes and catalysis of IDE substrates. a, Secondary structure of IDE substrates in the IDE-bound (top) or free (bottom) form. The N terminus and IDE catalytic cleft binding segment are coloured orange and red, respectively. The PDB accession codes for insulin are 1G7A and 1ZEH, those for A are 1AML and 1BA4, those for glucagon are 1GCN and 1KX6, and that for amylin is 1KUW. b, Sequence comparison of four IDE substrates. Arrows indicate the main cleavage sites of the substrate by IDE^1, ^26 (Supplementary Fig. 13). Amino acids that are underlined are observed in the crystal structures of substrate-bound IDE.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2006, 443, 870-874) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21265573 C.C.Huang, T.Orban, B.Jastrzebska, K.Palczewski, and J.J.Tesmer (2011).
Activation of G protein-coupled receptor kinase 1 involves interactions between its N-terminal region and its kinase domain.
  Biochemistry, 50, 1940-1949.
PDB code: 3qc9
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.  
21478864 T.T.Nguyen, S.C.Chang, I.Evnouchidou, I.A.York, C.Zikos, K.L.Rock, A.L.Goldberg, E.Stratikos, and L.J.Stern (2011).
Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1.
  Nat Struct Mol Biol, 18, 604-613.
PDB code: 3mdj
20135308 C.Jiang, Y.Feng, X.Huang, Y.Xu, Y.Zhang, N.Zhou, X.Shen, K.Chen, H.Jiang, and D.Liu (2010).
An enzyme-linked immunosorbent assay to compare the affinity of chemical compounds for β-amyloid peptide as a monomer.
  Anal Bioanal Chem, 396, 1745-1754.  
20300529 E.S.Song, D.W.Rodgers, and L.B.Hersh (2010).
A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties.
  PLoS One, 5, e9719.  
20498699 M.A.Leissring, E.Malito, S.Hedouin, L.Reinstatler, T.Sahara, S.O.Abdul-Hay, S.Choudhry, G.M.Maharvi, A.H.Fauq, M.Huzarska, P.S.May, S.Choi, T.P.Logan, B.E.Turk, L.C.Cantley, M.Manolopoulou, W.J.Tang, R.L.Stein, G.D.Cuny, and D.J.Selkoe (2010).
Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin.
  PLoS One, 5, e10504.
PDB code: 3e4a
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
20364150 N.Parmentier, V.Stroobant, D.Colau, P.de Diesbach, S.Morel, J.Chapiro, P.van Endert, and B.J.Van den Eynde (2010).
Production of an antigenic peptide by insulin-degrading enzyme.
  Nat Immunol, 11, 449-454.  
19896952 Q.Guo, M.Manolopoulou, Y.Bian, A.B.Schilling, and W.J.Tang (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.
PDB codes: 2wk3 3e4z 3e50 3hgz
20033747 R.P.Bora, M.Ozbil, and R.Prabhakar (2010).
Elucidation of insulin degrading enzyme catalyzed site specific hydrolytic cleavage of amyloid beta peptide: a comparative density functional theory study.
  J Biol Inorg Chem, 15, 485-495.  
19913481 A.E.Aleshin, S.Gramatikova, G.L.Hura, A.Bobkov, A.Y.Strongin, B.Stec, J.A.Tainer, R.C.Liddington, and J.W.Smith (2009).
Crystal and solution structures of a prokaryotic M16B peptidase: an open and shut case.
  Structure, 17, 1465-1475.
PDB code: 3hdi
19750477 B.J.Alper, J.W.Rowse, and W.K.Schmidt (2009).
Yeast Ste23p shares functional similarities with mammalian insulin-degrading enzymes.
  Yeast, 26, 595-610.  
19071160 B.J.Alper, and W.K.Schmidt (2009).
A capillary electrophoresis method for evaluation of Abeta proteolysis in vitro.
  J Neurosci Methods, 178, 40-45.  
19384407 C.Cabrol, M.A.Huzarska, C.Dinolfo, M.C.Rodriguez, L.Reinstatler, J.Ni, L.A.Yeh, G.D.Cuny, R.L.Stein, D.J.Selkoe, and M.A.Leissring (2009).
Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening.
  PLoS ONE, 4, e5274.  
19048247 G.Grasso, A.I.Bush, R.D'Agata, E.Rizzarelli, and G.Spoto (2009).
Enzyme solid-state support assays: a surface plasmon resonance and mass spectrometry coupled study of immobilized insulin degrading enzyme.
  Eur Biophys J, 38, 407-414.  
19127548 G.Grasso, E.Rizzarelli, and G.Spoto (2009).
The proteolytic activity of insulin-degrading enzyme: a mass spectrometry study.
  J Mass Spectrom, 44, 735-741.  
19416063 J.A.Hebda, and A.D.Miranker (2009).
The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes.
  Annu Rev Biophys, 38, 125-152.  
19144176 J.Zhao, L.Li, and M.A.Leissring (2009).
Insulin-degrading enzyme is exported via an unconventional protein secretion pathway.
  Mol Neurodegener, 4, 4.  
19196155 K.M.Chow, O.Gakh, I.C.Payne, M.A.Juliano, L.Juliano, G.Isaya, and L.B.Hersh (2009).
Mammalian pitrilysin: substrate specificity and mitochondrial targeting.
  Biochemistry, 48, 2868-2877.  
19808678 L.A.Ralat, M.Ren, A.B.Schilling, and W.J.Tang (2009).
Protective role of Cys-178 against the inactivation and oligomerization of human insulin-degrading enzyme by oxidation and nitrosylation.
  J Biol Chem, 284, 34005-34018.  
19321446 M.Manolopoulou, Q.Guo, E.Malito, A.B.Schilling, and W.J.Tang (2009).
Molecular Basis of Catalytic Chamber-assisted Unfolding and Cleavage of Human Insulin by Human Insulin-degrading Enzyme.
  J Biol Chem, 284, 14177-14188.
PDB codes: 2wby 2wc0
19560488 M.T.Neary, and R.L.Batterham (2009).
Gut hormones: implications for the treatment of obesity.
  Pharmacol Ther, 124, 44-56.  
19396426 O.Pivovarova, O.Gögebakan, A.F.Pfeiffer, and N.Rudovich (2009).
Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells.
  Diabetologia, 52, 1656-1664.  
19504624 R.K.Krishnankutty, S.S.Kukday, A.J.Castleberry, S.R.Breevoort, and W.K.Schmidt (2009).
Proteolytic processing of certain CaaX motifs can occur in the absence of the Rce1p and Ste24p CaaX proteases.
  Yeast, 26, 451-463.  
  19584300 Y.H.Chou, W.L.Kuo, M.R.Rosner, W.J.Tang, and R.D.Goldman (2009).
Structural changes in intermediate filament networks alter the activity of insulin-degrading enzyme.
  FASEB J, 23, 3734-3742.  
19117523 A.Bulloj, M.C.Leal, E.I.Surace, X.Zhang, H.Xu, M.D.Ledesma, E.M.Castano, and L.Morelli (2008).
Detergent resistant membrane-associated IDE in cultured cells and brain tissue: Relevance to Abeta and insulin degradation.
  Mol Neurodegener, 3, 22.  
18986166 E.Malito, L.A.Ralat, M.Manolopoulou, J.L.Tsay, N.L.Wadlington, and W.J.Tang (2008).
Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme.
  Biochemistry, 47, 12822-12834.
PDB code: 3cww
18470479 E.Malito, R.E.Hulse, and W.J.Tang (2008).
Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin.
  Cell Mol Life Sci, 65, 2574-2585.  
  18317569 G.D.Van Vickle, C.L.Esh, T.A.Kokjohn, R.L.Patton, W.M.Kalback, D.C.Luehrs, T.G.Beach, A.J.Newel, F.Lopera, B.Ghetti, R.Vidal, E.M.Castaño, and A.E.Roher (2008).
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease.
  Mol Med, 14, 184-194.  
18783335 G.Weirich, K.Mengele, C.Yfanti, A.Gkazepis, D.Hellmann, A.Welk, C.Giersig, W.L.Kuo, M.R.Rosner, W.J.Tang, and M.Schmitt (2008).
Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines.
  Biol Chem, 389, 1441-1445.  
18765820 J.D.Knight, J.A.Williamson, and A.D.Miranker (2008).
Interaction of membrane-bound islet amyloid polypeptide with soluble and crystalline insulin.
  Protein Sci, 17, 1850-1856.  
  19098445 M.B.de Tullio, L.Morelli, and E.M.Castaño (2008).
The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme: a biological perspective.
  Prion, 2, 51-56.  
18768474 M.J.Page, and E.Di Cera (2008).
Evolution of peptidase diversity.
  J Biol Chem, 283, 30010-30014.  
18942891 M.L.Hemming, J.E.Elias, S.P.Gygi, and D.J.Selkoe (2008).
Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements.
  PLoS Biol, 6, e257.  
18621727 M.Neant-Fery, R.D.Garcia-Ordoñez, T.P.Logan, D.J.Selkoe, L.Li, L.Reinstatler, and M.A.Leissring (2008).
Molecular basis for the thiol sensitivity of insulin-degrading enzyme.
  Proc Natl Acad Sci U S A, 105, 9582-9587.  
18583346 Q.Guo, J.E.Jureller, J.T.Warren, E.Solomaha, J.Florián, and W.J.Tang (2008).
Protein-protein docking and analysis reveal that two homologous bacterial adenylyl cyclase toxins interact with calmodulin differently.
  J Biol Chem, 283, 23836-23845.  
18411275 R.E.Llovera, M.de Tullio, L.G.Alonso, M.A.Leissring, S.B.Kaufman, A.E.Roher, G.de Prat Gay, L.Morelli, and E.M.Castaño (2008).
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide: implications for Alzheimer disease pathogenesis.
  J Biol Chem, 283, 17039-17048.  
18371220 S.Puehringer, M.Metlitzky, and R.Schwarzenbacher (2008).
The pyrroloquinoline quinone biosynthesis pathway revisited: a structural approach.
  BMC Biochem, 9, 8.  
18004559 V.Streltsov (2008).
X-ray absorption and diffraction studies of the metal binding sites in amyloid beta-peptide.
  Eur Biophys J, 37, 257-263.  
18095874 Y.Huet, J.Strassner, and A.Schaller (2008).
Cloning, expression and characterization of insulin-degrading enzyme from tomato (Solanum lycopersicum).
  Biol Chem, 389, 91-98.  
18353147 Y.Tatara, T.Namba, Y.Yamagata, T.Yoshida, T.Uchida, and E.Ichishima (2008).
Acid activation of protyrosinase from Aspergillus oryzae: homo-tetrameric protyrosinase is converted to active dimers with an essential intersubunit disulfide bond at acidic pH.
  Pigment Cell Melanoma Res, 21, 89-96.  
17434495 A.Pierres, A.Prakasam, D.Touchard, A.M.Benoliel, P.Bongrand, and D.Leckband (2007).
Dissecting subsecond cadherin bound states reveals an efficient way for cells to achieve ultrafast probing of their environment.
  FEBS Lett, 581, 1841-1846.  
17701350 C.Venugopal, M.A.Pappolla, and K.Sambamurti (2007).
Insulysin cleaves the APP cytoplasmic fragment at multiple sites.
  Neurochem Res, 32, 2225-2234.  
18085545 G.Grasso, E.Rizzarelli, and G.Spoto (2007).
AP/MALDI-MS complete characterization of the proteolytic fragments produced by the interaction of insulin degrading enzyme with bovine insulin.
  J Mass Spectrom, 42, 1590-1598.  
17613531 H.Im, M.Manolopoulou, E.Malito, Y.Shen, J.Zhao, M.Neant-Fery, C.Y.Sun, S.C.Meredith, S.S.Sisodia, M.A.Leissring, and W.J.Tang (2007).
Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE.
  J Biol Chem, 282, 25453-25463.
PDB codes: 2jbu 2jg4
17476590 K.S.Hui (2007).
Brain-specific aminopeptidase: from enkephalinase to protector against neurodegeneration.
  Neurochem Res, 32, 2062-2071.  
17653279 L.Jean, B.Thomas, A.Tahiri-Alaoui, M.Shaw, and D.J.Vaux (2007).
Heterologous amyloid seeding: revisiting the role of acetylcholinesterase in Alzheimer's disease.
  PLoS ONE, 2, e652.  
17553876 Q.Li, T.Krogmann, M.A.Ali, W.J.Tang, and J.I.Cohen (2007).
The amino terminus of varicella-zoster virus (VZV) glycoprotein E is required for binding to insulin-degrading enzyme, a VZV receptor.
  J Virol, 81, 8525-8532.  
17051198 M.A.Leissring, and D.J.Selkoe (2006).
Structural biology: enzyme target to latch on to.
  Nature, 443, 761-762.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.