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PDBsum entry 1s4b

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protein metals links
Hydrolase PDB id
1s4b
Jmol
Contents
Protein chain
654 a.a. *
Metals
_ZN
Waters ×474
* Residue conservation analysis
PDB id:
1s4b
Name: Hydrolase
Title: Crystal structure of human thimet oligopeptidase.
Structure: Thimet oligopeptidase. Chain: p. Synonym: endopeptidase 24.15, mp78. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: thop1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.00Å     R-factor:   0.201     R-free:   0.233
Authors: K.Ray,C.S.Hines,J.Coll-Rodriguez,D.W.Rodgers
Key ref:
K.Ray et al. (2004). Crystal structure of human thimet oligopeptidase provides insight into substrate recognition, regulation, and localization. J Biol Chem, 279, 20480-20489. PubMed id: 14998993 DOI: 10.1074/jbc.M400795200
Date:
15-Jan-04     Release date:   20-Jul-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P52888  (THOP1_HUMAN) -  Thimet oligopeptidase
Seq:
Struc:
 
Seq:
Struc:
689 a.a.
654 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.15  - Thimet oligopeptidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage of bonds with hydrophobic residues at P1, P2 and P3' and a small residue at P1' in substrates of 5 to 15 residues.
      Cofactor: Zinc
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     peptide metabolic process   2 terms 
  Biochemical function     protein binding     7 terms  

 

 
DOI no: 10.1074/jbc.M400795200 J Biol Chem 279:20480-20489 (2004)
PubMed id: 14998993  
 
 
Crystal structure of human thimet oligopeptidase provides insight into substrate recognition, regulation, and localization.
K.Ray, C.S.Hines, J.Coll-Rodriguez, D.W.Rodgers.
 
  ABSTRACT  
 
Thimet oligopeptidase (TOP) is a zinc metallopeptidase that metabolizes a number of bioactive peptides and degrades peptides released by the proteasome, limiting antigenic presentation by MHC class I molecules. We present the crystal structure of human TOP at 2.0-A resolution. The active site is located at the base of a deep channel that runs the length of the elongated molecule, an overall fold first seen in the closely related metallopeptidase neurolysin. Comparison of the two related structures indicates hinge-like flexibility and identifies elements near one end of the channel that adopt different conformations. Relatively few of the sequence differences between TOP and neurolysin map to the proposed substrate-binding site, and four of these variable residues may account for differences in substrate specificity. In addition, a loop segment (residues 599-611) in TOP differs in conformation and degree of order from the corresponding neurolysin loop, suggesting it may also play a role in activity differences. Cysteines thought to mediate covalent oligomerization of rat TOP, which can inactivate the enzyme, are found to be surface-accessible in the human enzyme, and additional cysteines (residues 321,350, and 644) may also mediate multimerization in the human homolog. Disorder in the N terminus of TOP indicates it may be involved in subcellular localization, but a potential nuclear import element is found to be part of a helix and, therefore, unlikely to be involved in transport. A large acidic patch on the surface could potentially mediate a protein-protein interaction, possibly through formation of a covalent linkage.
 
  Selected figure(s)  
 
Figure 3.
FIG. 3. Backbone superposition of TOP and neurolysin. Stereo view of superimposed thimet oligopeptidase (blue/red) and neurolysin (gold) C traces. Elements near the open end of the channel that show the greatest conformational differences are colored red in the TOP backbone representation.
Figure 4.
FIG. 4. Model of substrate peptide binding. A stereo view of the molecular surface representation of thimet oligopeptidase sectioned to show the floor of the active site channel is shown with the 13-residue substrate neurotensin modeled as described under "Model for Substrate Binding." The overall orientation is similar to Fig. 1A, and the N terminus of neurotensin is at the top of the figure. The image was produced with GRASP (73).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 20480-20489) copyright 2004.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21410325 L.Baginski, G.Tachon, F.Falson, J.S.Patton, U.Bakowsky, and C.Ehrhardt (2011).
Reverse transcription polymerase chain reaction (RT-PCR) analysis of proteolytic enzymes in cultures of human respiratory epithelial cells.
  J Aerosol Med Pulm Drug Deliv, 24, 89.  
19282285 D.A.Berti, C.Morano, L.C.Russo, L.M.Castro, F.M.Cunha, X.Zhang, J.Sironi, C.F.Klitzke, E.S.Ferro, and L.D.Fricker (2009).
Analysis of intracellular substrates and products of thimet oligopeptidase in human embryonic kidney 293 cells.
  J Biol Chem, 284, 14105-14116.  
18539138 C.E.Isaza, X.Zhong, L.E.Rosas, J.D.White, R.P.Chen, G.F.Liang, S.I.Chan, A.R.Satoskar, and M.K.Chan (2008).
A proposed role for Leishmania major carboxypeptidase in peptide catabolism.
  Biochem Biophys Res Commun, 373, 25-29.  
  18959747 L.A.Bruce, J.A.Sigman, D.Randall, S.Rodriguez, M.M.Song, Y.Dai, D.E.Elmore, A.Pabon, M.J.Glucksman, and A.J.Wolfson (2008).
Hydrogen bond residue positioning in the 599-611 loop of thimet oligopeptidase is required for substrate selection.
  FEBS J, 275, 5607-5617.  
  17277461 A.Kawasaki, H.Nakano, Y.Tsujimoto, H.Matsui, T.Shimizu, T.Nakatsu, H.Kato, and K.Watanabe (2007).
Crystallization and preliminary X-ray crystallographic studies of Pz peptidase A from Geobacillus collagenovorans MO-1.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 142-144.  
17620116 T.Paschoalin, A.K.Carmona, E.G.Rodrigues, V.Oliveira, H.P.Monteiro, M.A.Juliano, L.Juliano, and L.R.Travassos (2007).
Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth.
  Mol Cancer, 6, 44.  
17284829 Y.Sugihara, A.Kawasaki, Y.Tsujimoto, H.Matsui, and K.Watanabe (2007).
Potencies of phosphine peptide inhibitors of mammalian thimet oligopeptidase and neurolysin on two bacterial pz peptidases.
  Biosci Biotechnol Biochem, 71, 594-597.  
16181326 L.Saveanu, O.Carroll, Y.Hassainya, and P.van Endert (2005).
Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation.
  Immunol Rev, 207, 42-59.  
15937176 R.Miyake, Y.Shigeri, Y.Tatsu, N.Yumoto, M.Umekawa, Y.Tsujimoto, H.Matsui, and K.Watanabe (2005).
Two thimet oligopeptidase-like Pz peptidases produced by a collagen-degrading thermophile, Geobacillus collagenovorans MO-1.
  J Bacteriol, 187, 4140-4148.  
16181327 T.A.Groothuis, A.C.Griekspoor, J.J.Neijssen, C.A.Herberts, and J.J.Neefjes (2005).
MHC class I alleles and their exploration of the antigen-processing machinery.
  Immunol Rev, 207, 60-76.  
15955058 V.Oliveira, P.A.Garrido, C.C.Rodrigues, A.Colquhoun, L.M.Castro, P.C.Almeida, C.S.Shida, M.A.Juliano, L.Juliano, A.C.Camargo, S.Hyslop, J.L.Roberts, V.Grum-Tokars, M.J.Glucksman, and E.S.Ferro (2005).
Calcium modulates endopeptidase 24.15 (EC 3.4.24.15) membrane association, secondary structure and substrate specificity.
  FEBS J, 272, 2978-2992.  
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.