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Hydrolase PDB id
1nu6
Jmol
Contents
Protein chains
728 a.a. *
Ligands
NAG ×7
NDG
Metals
_HG ×6
Waters ×322
* Residue conservation analysis
PDB id:
1nu6
Name: Hydrolase
Title: Crystal structure of human dipeptidyl peptidase iv (dpp-iv)
Structure: Dipeptidyl peptidase iv. Chain: a, b. Synonym: dpp iv. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Biol. unit: Dimer (from PQS)
Resolution:
2.10Å     R-factor:   0.217     R-free:   0.266
Authors: M.Hennig,M.Stihle,R.Thoma,A.Ruf
Key ref:
R.Thoma et al. (2003). Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure, 11, 947-959. PubMed id: 12906826 DOI: 10.1016/S0969-2126(03)00160-6
Date:
31-Jan-03     Release date:   26-Aug-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P27487  (DPP4_HUMAN) -  Dipeptidyl peptidase 4
Seq:
Struc: 		 
Seq:
Struc: 		766 a.a.
728 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.14.5  - Dipeptidyl-peptidase Iv.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, from a polypeptide, preferentially when Xbb is Pro, provided Xcc is neither Pro nor hydroxyproline.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   18 terms 
  Biological process     establishment of localization   11 terms 
  Biochemical function     protein binding     13 terms  

 

 
DOI no: 10.1016/S0969-2126(03)00160-6 Structure 11:947-959 (2003)
PubMed id: 12906826  
 
 
Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV.
R.Thoma, B.Löffler, M.Stihle, W.Huber, A.Ruf, M.Hennig.
 
  ABSTRACT  
 
Inhibition of dipeptidyl peptidase IV (DPP-IV), the main glucagon-like peptide 1 (GLP1)-degrading enzyme, has been proposed for the treatment of type II diabetes. We expressed and purified the ectodomain of human DPP-IV in Pichia pastoris and determined the X-ray structure at 2.1 A resolution. The enzyme consists of two domains, the catalytic domain, with an alpha/beta hydrolase fold, and a beta propeller domain with an 8-fold repeat of a four-strand beta sheet motif. The beta propeller domain contributes two important functions to the molecule that have not been reported for such structures, an extra beta sheet motif that forms part of the dimerization interface and an additional short helix with a double Glu sequence motif. The Glu motif provides recognition and a binding site for the N terminus of the substrates, as revealed by the complex structure with diprotin A, a substrate with low turnover that is trapped in the tetrahedral intermediate of the reaction in the crystal.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. Access to the Active SiteSchematic view on the subunit of DPP-IV with the active site surface colored according to the atom types. The substrate diprotin A is shown with white carbons indicating the substrate binding site. Arrows illustrate that the substrate may enter the active site at the well-accessible and open active site cleft and that the dipeptidic product of the catalytic reaction may leave the active site cavity via the narrower tunnel that is formed by the b propeller.
 
  The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 947-959) copyright 2003.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21465558 C.Li, J.Shen, W.Li, C.Lu, G.Liu, and Y.Tang (2011).
Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations.
  Proteins, 79, 1800-1809.  
20029928 H.Zettl, M.Schubert-Zsilavecz, and D.Steinhilber (2010).
Medicinal Chemistry of Incretin Mimetics and DPP-4 Inhibitors.
  ChemMedChem, 5, 179-185.  
20572019 K.M.Chung, J.H.Cheng, C.S.Suen, C.H.Huang, C.H.Tsai, L.H.Huang, Y.R.Chen, A.H.Wang, W.T.Jiaang, M.J.Hwang, and X.Chen (2010).
The dimeric transmembrane domain of prolyl dipeptidase DPP-IV contributes to its quaternary structure and enzymatic activities.
  Protein Sci, 19, 1627-1638.  
20444688 M.Li, C.Chen, D.R.Davies, and T.K.Chiu (2010).
Induced-fit mechanism for prolyl endopeptidase.
  J Biol Chem, 285, 21487-21495.
PDB codes: 3iuj 3iul 3ium 3iun 3iuq 3iur 3ivm
19267232 C.X.Hu, H.Huang, L.Zhang, Y.Huang, Z.F.Shen, K.D.Cheng, G.H.Du, and P.Zhu (2009).
A new screening method based on yeast-expressed human dipeptidyl peptidase IV and discovery of novel inhibitors.
  Biotechnol Lett, 31, 979-984.  
18550518 P.K.Baral, N.Jajcanin-Jozić, S.Deller, P.Macheroux, M.Abramić, and K.Gruber (2008).
The first structure of dipeptidyl-peptidase III provides insight into the catalytic mechanism and mode of substrate binding.
  J Biol Chem, 283, 22316-22324.  
17704566 C.Oefner, S.Pierau, H.Schulz, and G.E.Dale (2007).
Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
  Acta Crystallogr D Biol Crystallogr, 63, 975-981.
PDB code: 2qpj
17068815 C.Rummey, and G.Metz (2007).
Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site.
  Proteins, 66, 160-171.  
17492130 H.Hiramatsu, K.Kyono, A.Yamamoto, K.Saeki, H.Shima, S.Sugiyama, K.Inaka, and R.Shimizu (2007).
Crystal structures of human dipeptidyl peptidase IV in its apo and diprotin B-complexed forms.
  Acta Biochim Biophys Sin (Shanghai), 39, 335-343.  
17618469 J.Zeng, G.Liu, Y.Tang, and H.Jiang (2007).
3D-QSAR studies on fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors by CoMFA and CoMSIA.
  J Mol Model, 13, 993.  
17338643 M.Barsun, N.Jajcanin, B.Vukelić, J.Spoljarić, and M.Abramić (2007).
Human dipeptidyl peptidase III acts as a post-proline-cleaving enzyme on endomorphins.
  Biol Chem, 388, 343-348.  
17298553 V.S.Lee, W.C.Tu, T.R.Jinn, C.C.Peng, L.J.Lin, and J.T.Tzen (2007).
Molecular cloning of the precursor polypeptide of mastoparan B and its putative processing enzyme, dipeptidyl peptidase IV, from the black-bellied hornet, Vespa basalis.
  Insect Mol Biol, 16, 231-237.  
16410248 C.Y.Edosada, C.Quan, C.Wiesmann, T.Tran, D.Sutherlin, M.Reynolds, J.M.Elliott, H.Raab, W.Fairbrother, and B.B.Wolf (2006).
Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity.
  J Biol Chem, 281, 7437-7444.  
17040910 H.J.Lee, Y.S.Chen, C.Y.Chou, C.H.Chien, C.H.Lin, G.G.Chang, and X.Chen (2006).
Investigation of the dimer interface and substrate specificity of prolyl dipeptidase DPP8.
  J Biol Chem, 281, 38653-38662.  
17112720 P.R.Mittl, and M.G.Grütter (2006).
Opportunities for structure-based design of protease-directed drugs.
  Curr Opin Struct Biol, 16, 769-775.  
  17119608 C.J.Chihara, C.Song, G.LaMonte, K.Fetalvero, K.Hinchman, H.Phan, M.Pineda, K.Robinson, and G.P.Schneider (2005).
Identification and partial characterization of the enzyme of omega: one of five putative DPP IV genes in Drosophila melanogaster.
  J Insect Sci, 5, 26.  
15819895 P.Rigolet, X.G.Xi, S.Rety, and J.F.Chich (2005).
The structural comparison of the bacterial PepX and human DPP-IV reveals sites for the design of inhibitors of PepX activity.
  FEBS J, 272, 2050-2059.  
15549676 R.L.Rich, and D.G.Myszka (2005).
Survey of the year 2003 commercial optical biosensor literature.
  J Mol Recognit, 18, 1.  
15695814 W.A.Weihofen, J.Liu, W.Reutter, W.Saenger, and H.Fan (2005).
Crystal structures of HIV-1 Tat-derived nonapeptides Tat-(1-9) and Trp2-Tat-(1-9) bound to the active site of dipeptidyl-peptidase IV (CD26).
  J Biol Chem, 280, 14911-14917.
PDB codes: 2bgn 2bgr
15997470 W.Huber (2005).
A new strategy for improved secondary screening and lead optimization using high-resolution SPR characterization of compound-target interactions.
  J Mol Recognit, 18, 273-281.  
15255191 H.Hiramatsu, A.Yamamoto, K.Kyono, Y.Higashiyama, C.Fukushima, H.Shima, S.Sugiyama, K.Inaka, and R.Shimizu (2004).
The crystal structure of human dipeptidyl peptidase IV (DPPIV) complex with diprotin A.
  Biol Chem, 385, 561-564.
PDB code: 1wcy
15175333 J.R.Bjelke, J.Christensen, S.Branner, N.Wagtmann, C.Olsen, A.B.Kanstrup, and H.B.Rasmussen (2004).
Tyrosine 547 constitutes an essential part of the catalytic mechanism of dipeptidyl peptidase IV.
  J Biol Chem, 279, 34691-34697.
PDB codes: 1tk3 1tkr 1to7 1u8e
14718659 K.Aertgeerts, S.Ye, M.G.Tennant, M.L.Kraus, J.Rogers, B.C.Sang, R.J.Skene, D.R.Webb, and G.S.Prasad (2004).
Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation.
  Protein Sci, 13, 412-421.
PDB codes: 1r9m 1r9n
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 codes are shown on the right.