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Hydrolase PDB id
1n1m
Jmol
Contents
Protein chains
726 a.a. *
Ligands
NAG-NDG-FUC
NDG-NAG-FUC
NAG-NAG ×3
NAG-NDG-MAN
NAG ×3
A3M ×2
NAG-FUC
NDG-NAG
NAG-NAG-BMA ×2
NDG-NDG
Metals
_HG ×4
Waters ×931
* Residue conservation analysis
PDB id:
1n1m
Name: Hydrolase
Title: Human dipeptidyl peptidase iv/cd26 in complex with an inhibi
Structure: Dipeptidyl peptidase iv soluble form. Chain: a, b. Fragment: extracellular domain. Synonym: dpp iv, t-cell activation antigen cd26, tp103, ade deaminase complexing protein-2, adabp. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: hi5.
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.211     R-free:   0.263
Authors: H.B.Rasmussen,S.Branner,F.C.Wiberg,N.R.Wagtmann
Key ref:
H.B.Rasmussen et al. (2003). Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol, 10, 19-25. PubMed id: 12483204 DOI: 10.1038/nsb882
Date:
18-Oct-02     Release date:   27-Dec-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P27487  (DPP4_HUMAN) -  Dipeptidyl peptidase 4
Seq:
Struc: 		 
Seq:
Struc: 		766 a.a.
726 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: 10.1038/nsb882 Nat Struct Biol 10:19-25 (2003)
PubMed id: 12483204  
 
 
Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog.
H.B.Rasmussen, S.Branner, F.C.Wiberg, N.Wagtmann.
 
  ABSTRACT  
 
Dipeptidyl peptidase IV (DPP-IV/CD26) is a multifunctional type II transmembrane serine peptidase. This enzyme contributes to the regulation of various physiological processes, including blood sugar homeostasis, by cleaving peptide hormones, chemokines and neuropeptides. We have determined the 2.5 A structure of the extracellular region of DPP-IV in complex with the inhibitor valine-pyrrolidide. The catalytic site is located in a large cavity formed between the alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain. Both domains participate in inhibitor binding. The structure indicates how substrate specificity is achieved and reveals a new and unexpected opening to the active site.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Structural comparison of DPP-IV and POP. The eight (DPP-IV) and seven (POP) bladed -propeller domains are illustrated by solid ribbon and colored by blade number. The / -hydrolase domain is gray. a, DPP-IV viewed from the side. Glu205, Glu206 and Ser630 are illustrated by ball and stick (red). The extended arm is yellow, and the horizontal helix holding Glu205 and Glu206 is black. b, DPP-IV viewed from the bottom. c, POP viewed from the side. The N-terminal extension relative to DPP-IV is dark gray. d, POP viewed from the bottom, with Ser554 illustrated in ball and stick (red). 		Figure 4.
Figure 4. Active site of DPP-IV. a, Stereo drawing of the active site of DPP-IV. Val-Pyr is shown in CPK, with selected residues are shown in stick and colored by element type as in Fig. 1a. Hydrogen bonds/electrostatic interactions are shown with dotted lines. Glu205 and Glu206 coordinate the N terminus. Arg125 and Asn710 coordinate the carbonyl group of the peptide bond before the cleavage point. The pyrollidide ring is packed between Tyr547, Tyr762 and Tyr666. The valine moiety of the inhibitor has no contacts but points towards the pocket. b, Val-Pyr is shown in thick sticks and selected residues (as in a) in thin sticks. The initial MAD electron density map after SHARP refinement at 2.5 Å resolution is overlaid contoured at 1 (blue) and 2 (red). c, The chemical structure of the inhibitor Val-Pyr.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 19-25) copyright 2003.  
  Figures were selected by an automated process.  

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.
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21198750 D.M.Yu, L.Slaitini, V.Gysbers, A.G.Riekhoff, T.Kähne, H.M.Knott, I.De Meester, C.A.Abbott, G.W.McCaughan, and M.D.Gorrell (2011).
Soluble CD26 / dipeptidyl peptidase IV enhances human lymphocyte proliferation in vitro independent of dipeptidyl peptidase enzyme activity and adenosine deaminase binding.
  Scand J Immunol, 73, 102-111.  
21194362 S.Ansorge, K.Nordhoff, U.Bank, A.Heimburg, H.Julius, D.Breyer, A.Thielitz, D.Reinhold, and M.Täger (2011).
Novel aspects of cellular action of dipeptidyl peptidase IV/CD26.
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20941418 G.Palmieri, E.Langella, M.Gogliettino, M.Saviano, G.Pocsfalvi, and M.Rossi (2010).
A novel class of protease targets of phosphatidylethanolamine-binding proteins (PEBP): a study of the acylpeptide hydrolase and the PEBP inhibitor from the archaeon Sulfolobus solfataricus.
  Mol Biosyst, 6, 2498-2507.  
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.
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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
20536396 M.R.Pitman, R.I.Menz, and C.A.Abbott (2010).
Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8).
  Biol Chem, 391, 959-972.  
20540760 S.M.Soisson, S.B.Patel, P.D.Abeywickrema, N.J.Byrne, R.E.Diehl, D.L.Hall, R.E.Ford, J.C.Reid, K.W.Rickert, J.M.Shipman, S.Sharma, and K.J.Lumb (2010).
Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase.
  BMC Struct Biol, 10, 16.
PDB code: 3n2z
19122660 E.M.Quistgaard, P.Madsen, M.K.Grøftehauge, P.Nissen, C.M.Petersen, and S.S.Thirup (2009).
Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain.
  Nat Struct Mol Biol, 16, 96-98.
PDB code: 3f6k
19126297 H.Fuchs, J.P.Tillement, S.Urien, A.Greischel, and W.Roth (2009).
Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans.
  J Pharm Pharmacol, 61, 55-62.  
19562682 H.Fuchs, R.Binder, and A.Greischel (2009).
Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats.
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18456553 K.Ohnuma, N.H.Dang, and C.Morimoto (2008).
Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function.
  Trends Immunol, 29, 295-301.  
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.  
18227430 W.J.Metzler, J.Yanchunas, C.Weigelt, K.Kish, H.E.Klei, D.Xie, Y.Zhang, M.Corbett, J.K.Tamura, B.He, L.G.Hamann, M.S.Kirby, and J.Marcinkeviciene (2008).
Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation.
  Protein Sci, 17, 240-250.
PDB code: 3bjm
18820015 Y.Nakajima, K.Ito, T.Toshima, T.Egawa, H.Zheng, H.Oyama, Y.F.Wu, E.Takahashi, K.Kyono, and T.Yoshimoto (2008).
Dipeptidyl aminopeptidase IV from Stenotrophomonas maltophilia exhibits activity against a substrate containing a 4-hydroxyproline residue.
  J Bacteriol, 190, 7819-7829.
PDB code: 2ecf
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.  
17592366 D.Detel, M.Persić, and J.Varljen (2007).
Serum and intestinal dipeptidyl peptidase IV (DPP IV/CD26) activity in children with celiac disease.
  J Pediatr Gastroenterol Nutr, 45, 65-70.  
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.  
17242511 J.Bosch, T.Tamura, N.Tamura, W.Baumeister, and L.O.Essen (2007).
The beta-propeller domain of the trilobed protease from Pyrococcus furiosus reveals an open Velcro topology.
  Acta Crystallogr D Biol Crystallogr, 63, 179-187.
PDB code: 2gop
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.  
17287217 K.Ohnuma, M.Uchiyama, T.Yamochi, K.Nishibashi, O.Hosono, N.Takahashi, S.Kina, H.Tanaka, X.Lin, N.H.Dang, and C.Morimoto (2007).
Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1.
  J Biol Chem, 282, 10117-10131.  
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.  
17676345 R.R.Pissurlenkar, M.S.Shaikh, and E.C.Coutinho (2007).
3D-QSAR studies of Dipeptidyl peptidase IV inhibitors using a docking based alignment.
  J Mol Model, 13, 1047-1071.  
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.  
  16880564 D.Rea, C.Hazell, N.W.Andrews, R.E.Morty, and V.Fülöp (2006).
Expression, purification and preliminary crystallographic analysis of oligopeptidase B from Trypanosoma brucei.
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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.  
16885166 K.Ito, Y.Nakajima, Y.Onohara, M.Takeo, K.Nakashima, F.Matsubara, T.Ito, and T.Yoshimoto (2006).
Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition.
  J Biol Chem, 281, 33664-33676.
PDB codes: 2dq6 2dqm
16478473 N.Bilodeau, A.Fiset, G.G.Poirier, S.Fortier, M.C.Gingras, J.N.Lavoie, and R.L.Faure (2006).
Insulin-dependent phosphorylation of DPP IV in liver. Evidence for a role of compartmentalized c-Src.
  FEBS J, 273, 992.  
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.  
15671030 E.Zagha, A.Ozaita, S.Y.Chang, M.S.Nadal, U.Lin, M.J.Saganich, T.McCormack, K.O.Akinsanya, S.Y.Qi, and B.Rudy (2005).
DPP10 modulates Kv4-mediated A-type potassium channels.
  J Biol Chem, 280, 18853-18861.  
  16511202 H.Wright, A.L.Kiss, Z.Szeltner, L.Polgár, and V.Fülöp (2005).
Crystallization and preliminary crystallographic analysis of porcine acylaminoacyl peptidase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 942-944.  
15971204 M.Fuxreiter, C.Magyar, T.Juhász, Z.Szeltner, L.Polgár, and I.Simon (2005).
Flexibility of prolyl oligopeptidase: molecular dynamics and molecular framework analysis of the potential substrate pathways.
  Proteins, 60, 504-512.  
15678420 M.Groll, M.Bochtler, H.Brandstetter, T.Clausen, and R.Huber (2005).
Molecular machines for protein degradation.
  Chembiochem, 6, 222-256.  
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.  
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
15448155 C.H.Chien, L.H.Huang, C.Y.Chou, Y.S.Chen, Y.S.Han, G.G.Chang, P.H.Liang, and X.Chen (2004).
One site mutation disrupts dimer formation in human DPP-IV proteins.
  J Biol Chem, 279, 52338-52345.  
15388936 D.Rea, A.M.Lambeir, Y.Kumagai, I.De Meester, S.Scharpé, and V.Fülöp (2004).
Expression, purification and preliminary crystallographic analysis of dipeptidyl peptidase IV from Porphyromonas gingivalis.
  Acta Crystallogr D Biol Crystallogr, 60, 1871-1873.  
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
14691230 K.Aertgeerts, S.Ye, L.Shi, S.G.Prasad, D.Witmer, E.Chi, B.C.Sang, R.A.Wijnands, D.R.Webb, and R.V.Swanson (2004).
N-linked glycosylation of dipeptidyl peptidase IV (CD26): effects on enzyme activity, homodimer formation, and adenosine deaminase binding.
  Protein Sci, 13, 145-154.  
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
15353589 K.Ohnuma, T.Yamochi, M.Uchiyama, K.Nishibashi, N.Yoshikawa, N.Shimizu, S.Iwata, H.Tanaka, N.H.Dang, and C.Morimoto (2004).
CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1.
  Proc Natl Acad Sci U S A, 101, 14186-14191.  
15016824 M.Gonzalez-Gronow, M.S.Hershfield, F.X.Arredondo-Vega, and S.V.Pizzo (2004).
Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells.
  J Biol Chem, 279, 20993-20998.  
15213224 W.A.Weihofen, J.Liu, W.Reutter, W.Saenger, and H.Fan (2004).
Crystal structure of CD26/dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface.
  J Biol Chem, 279, 43330-43335.
PDB code: 1w1i
14719797 J.Bär, A.Weber, T.Hoffmann, J.Stork, M.Wermann, L.Wagner, S.Aust, B.Gerhartz, and H.U.Demuth (2003).
Characterisation of human dipeptidyl peptidase IV expressed in Pichia pastoris. A structural and mechanistic comparison between the recombinant human and the purified porcine enzyme.
  Biol Chem, 384, 1553-1563.  
  12941425 J.S.Rosenblum, and J.W.Kozarich (2003).
Prolyl peptidases: a serine protease subfamily with high potential for drug discovery.
  Curr Opin Chem Biol, 7, 496-504.  
12490884 M.D.Gorrell (2003).
First bite.
  Nat Struct Biol, 10, 3-5.  
12690074 M.Engel, T.Hoffmann, L.Wagner, M.Wermann, U.Heiser, R.Kiefersauer, R.Huber, W.Bode, H.U.Demuth, and H.Brandstetter (2003).
The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism.
  Proc Natl Acad Sci U S A, 100, 5063-5068.
PDB codes: 1orv 1orw
  12906826 R.Thoma, B.Löffler, M.Stihle, W.Huber, A.Ruf, and M.Hennig (2003).
Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV.
  Structure, 11, 947-959.
PDB codes: 1nu6 1nu8
12752434 S.Lorey, A.Stöckel-Maschek, J.Faust, W.Brandt, B.Stiebitz, M.D.Gorrell, T.Kähne, C.Mrestani-Klaus, S.Wrenger, D.Reinhold, S.Ansorge, and K.Neubert (2003).
Different modes of dipeptidyl peptidase IV (CD26) inhibition by oligopeptides derived from the N-terminus of HIV-1 Tat indicate at least two inhibitor binding sites.
  Eur J Biochem, 270, 2147-2156.  
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.