spacer
spacer

PDBsum entry 1k3b

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
1k3b
Jmol
Contents
Protein chains
119 a.a. *
164 a.a. *
69 a.a. *
Ligands
NAG
SO4 ×3
Metals
_CL
Waters ×464
* Residue conservation analysis
PDB id:
1k3b
Name: Hydrolase
Title: Crystal structure of human dipeptidyl peptidase i (cathepsin exclusion domain added to an endopeptidase framework create machine for activation of granular serine proteases
Structure: Dipeptydil-peptidase i exclusion domain. Chain: a. Synonym: dppi, cathepsin c, residual propart. Engineered: yes. Dipeptydil-peptidase i light chain. Chain: b. Synonym: dppi, cathepsin c, beta chain. Engineered: yes. Dipeptydil-peptidase i heavy chain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five. Expression_system_cell: insect cell(invitrogen).
Biol. unit: Dodecamer (from PDB file)
Resolution:
2.15Å     R-factor:   0.190     R-free:   0.231
Authors: D.Turk,V.Janjic,I.Stern,M.Podobnik,D.Lamba,S.W.Dahl,C.Laurit J.Pedersen,V.Turk,B.Turk
Key ref:
D.Turk et al. (2001). Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. EMBO J, 20, 6570-6582. PubMed id: 11726493 DOI: 10.1093/emboj/20.23.6570
Date:
02-Oct-01     Release date:   02-Apr-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P53634  (CATC_HUMAN) -  Dipeptidyl peptidase 1
Seq:
Struc:
463 a.a.
119 a.a.
Protein chain
Pfam   ArchSchema ?
P53634  (CATC_HUMAN) -  Dipeptidyl peptidase 1
Seq:
Struc:
463 a.a.
164 a.a.
Protein chain
Pfam   ArchSchema ?
P53634  (CATC_HUMAN) -  Dipeptidyl peptidase 1
Seq:
Struc:
463 a.a.
69 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C: E.C.3.4.14.1  - Dipeptidyl-peptidase I.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, except when Xaa is Arg or Lys, or Xbb or Xcc is Pro.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     cysteine-type peptidase activity     1 term  

 

 
DOI no: 10.1093/emboj/20.23.6570 EMBO J 20:6570-6582 (2001)
PubMed id: 11726493  
 
 
Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases.
D.Turk, V.Janjić, I.Stern, M.Podobnik, D.Lamba, S.W.Dahl, C.Lauritzen, J.Pedersen, V.Turk, B.Turk.
 
  ABSTRACT  
 
Dipeptidyl peptidase I (DPPI) or cathepsin C is the physiological activator of groups of serine proteases from immune and inflammatory cells vital for defense of an organism. The structure presented shows how an additional domain transforms the framework of a papain-like endopeptidase into a robust oligomeric protease-processing enzyme. The tetrahedral arrangement of the active sites exposed to solvent allows approach of proteins in their native state; the massive body of the exclusion domain fastened within the tetrahedral framework excludes approach of a polypeptide chain apart from its termini; and the carboxylic group of Asp1 positions the N-terminal amino group of the substrate. Based on a structural comparison and interactions within the active site cleft, it is suggested that the exclusion domain originates from a metallo-protease inhibitor. The location of missense mutations, characterized in people suffering from Haim-Munk and Papillon-Lefevre syndromes, suggests how they disrupt the fold and function of the enzyme.
 
  Selected figure(s)  
 
Figure 3.
Figure 3 Active site cleft of DPPI with a bound model of the N-terminal sequence ERIIGG from the biological substrate, granzyme A. (A) Stereo view: covalent bonds of papain-like domains and the exclusion domain are shown in the colors used in Figure 1C. Covalent bonds of the substrate model are shown as yellow sticks. Corresponding carbon atoms are shown as balls using the covalent bond color scheme. The chloride ion is shown as a large green sphere. Oxygen, nitrogen and sulfur atoms are shown as red, blue and yellow spheres, respectively. The residues relevant for substrate binding are marked and hydrogen bonds are shown as white broken lines. The molecular surface was generated with GRASP (Nicholls et al., 1991); the figure was prepared in MAIN (Turk, 1992) and rendered with RENDER (Merritt and Bacon, 1997). (B) Schematic presentation. The color codes are the same as in (A).
Figure 4.
Figure 4 Features of papain-like exopeptidases. A view towards the active site clefts of superimposed papain-like proteases. The underlying molecular surface of cathepsin L, shown in white, is used to demonstrate an endopeptidase active site cleft, which is blocked by features of the exopeptidase structures. The surface of the catalytic cysteine is colored in yellow. Chain traces of cathepsins B, X and H are shown in green, cyan and purple, respectively. Chain traces of papain-like domains of DPPI are shown in dark blue, whereas for the chain trace of the exclusion domain the color code is the same as in Figure 1. The bleomycin hydrolase chain trace is not shown for reasons of clarity, although its C-terminal residues superimpose almost perfectly with the C-terminal residues of the cathepsin H mini-chain (purple).
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 6570-6582) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21360816 S.S.Mahajan, E.Deu, E.M.Lauterwasser, M.J.Leyva, J.A.Ellman, M.Bogyo, and A.R.Renslo (2011).
A fragmenting hybrid approach for targeted delivery of multiple therapeutic agents to the malaria parasite.
  ChemMedChem, 6, 415-419.  
20883454 D.de Sanctis, J.M.Inácio, P.F.Lindley, I.de Sá-Nogueira, and I.Bento (2010).
New evidence for the role of calcium in the glycosidase reaction of GH43 arabinanases.
  FEBS J, 277, 4562-4574.
PDB codes: 2x8f 2x8s 2x8t
20797610 E.Deu, M.J.Leyva, V.E.Albrow, M.J.Rice, J.A.Ellman, and M.Bogyo (2010).
Functional studies of Plasmodium falciparum dipeptidyl aminopeptidase I using small molecule inhibitors and active site probes.
  Chem Biol, 17, 808-819.  
20921628 J.Reiser, B.Adair, and T.Reinheckel (2010).
Specialized roles for cysteine cathepsins in health and disease.
  J Clin Invest, 120, 3421-3431.  
20860624 M.Renko, U.Požgan, D.Majera, and D.Turk (2010).
Stefin A displaces the occluding loop of cathepsin B only by as much as required to bind to the active site cleft.
  FEBS J, 277, 4338-4345.
PDB code: 3k9m
  19933375 N.N.Trivedi, and G.H.Caughey (2010).
Mast cell peptidases: chameleons of innate immunity and host defense.
  Am J Respir Cell Mol Biol, 42, 257-267.  
19167329 C.Ruiz-Canada, D.J.Kelleher, and R.Gilmore (2009).
Cotranslational and posttranslational N-glycosylation of polypeptides by distinct mammalian OST isoforms.
  Cell, 136, 272-283.  
18815839 H.Jiang, Y.M.Cai, L.Q.Chen, X.W.Zhang, S.N.Hu, and Q.Wang (2009).
Functional Annotation and Analysis of Expressed Sequence Tags from the Hepatopancreas of Mitten Crab (Eriocheir sinensis).
  Mar Biotechnol (NY), 11, 317-326.  
18945301 M.Castori, S.Madonna, L.Giannetti, G.Floriddia, M.Milioto, S.Amato, and D.Castiglia (2009).
Novel CTSC mutations in a patient with Papillon-Lefèvre syndrome with recurrent pyoderma and minimal oral and palmoplantar involvement.
  Br J Dermatol, 160, 881-883.  
19816003 M.Kurban, M.Wajid, Y.Shimomura, R.Bahhady, A.G.Kibbi, and A.M.Christiano (2009).
Evidence for a founder mutation in the cathepsin C gene in three families with Papillon-Lefèvre syndrome.
  Dermatology, 219, 289-294.  
18622569 S.Roberts, G.Goetz, S.White, and F.Goetz (2009).
Analysis of Genes Isolated from Plated Hemocytes of the Pacific Oyster, Crassostreas gigas.
  Mar Biotechnol (NY), 11, 24-44.  
19627523 T.C.Hart, and P.S.Hart (2009).
Genetic studies of craniofacial anomalies: clinical implications and applications.
  Orthod Craniofac Res, 12, 212-220.  
18256700 G.Hamilton, J.D.Colbert, A.W.Schuettelkopf, and C.Watts (2008).
Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis.
  EMBO J, 27, 499-508.  
18307834 K.Hirasaka, K.Tokuoka, R.Nakao, C.Yamada, M.Oarada, T.Imagawa, K.Ishidoh, Y.Okumura, K.Kishi, and T.Nikawa (2008).
Cathepsin C propeptide interacts with intestinal alkaline phosphatase and heat shock cognate protein 70 in human Caco-2 cells.
  J Physiol Sci, 58, 105-111.  
18445589 K.N.DuBois, M.Abodeely, J.Sakanari, C.S.Craik, M.Lee, J.H.McKerrow, and M.Sajid (2008).
Identification of the major cysteine protease of Giardia and its role in encystation.
  J Biol Chem, 283, 18024-18031.  
18979629 L.Böhme, J.W.Bär, T.Hoffmann, S.Manhart, H.H.Ludwig, F.Rosche, and H.U.Demuth (2008).
Isoaspartate residues dramatically influence substrate recognition and turnover by proteases.
  Biol Chem, 389, 1043-1053.  
18362148 M.Mihelic, A.Dobersek, G.Guncar, and D.Turk (2008).
Inhibitory fragment from the p41 form of invariant chain can regulate activity of cysteine cathepsins in antigen presentation.
  J Biol Chem, 283, 14453-14460.  
18523964 R.Latajka, M.Jewginski, M.Makowski, M.Pawełczak, T.Huber, N.Sewald, and P.Kafarski (2008).
Pentapeptides containing two dehydrophenylalanine residues--synthesis, structural studies and evaluation of their activity towards cathepsin C.
  J Pept Sci, 14, 1084-1095.  
17976006 T.Zavasnik-Bergant, and B.Turk (2007).
Cysteine proteases: destruction ability versus immunomodulation capacity in immune cells.
  Biol Chem, 388, 1141-1149.  
17164247 X.Que, J.C.Engel, D.Ferguson, A.Wunderlich, S.Tomavo, and S.L.Reed (2007).
Cathepsin Cs are key for the intracellular survival of the protozoan parasite, Toxoplasma gondii.
  J Biol Chem, 282, 4994-5003.  
16955069 B.Turk (2006).
Targeting proteases: successes, failures and future prospects.
  Nat Rev Drug Discov, 5, 785-799.  
16895486 J.Mallen-St Clair, G.P.Shi, R.E.Sutherland, H.A.Chapman, G.H.Caughey, and P.J.Wolters (2006).
Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice.
  Biol Chem, 387, 1143-1146.  
15635097 C.Appenzeller-Herzog, B.Nyfeler, P.Burkhard, I.Santamaria, C.Lopez-Otin, and H.P.Hauri (2005).
Carbohydrate- and conformation-dependent cargo capture for ER-exit.
  Mol Biol Cell, 16, 1258-1267.  
15857107 C.J.Lux, B.Kugel, G.Komposch, S.Pohl, and P.Eickholz (2005).
Orthodontic treatment in a patient with Papillon-Lefèvre syndrome.
  J Periodontol, 76, 642-650.  
15195995 A.Rossi, Q.Deveraux, B.Turk, and A.Sali (2004).
Comprehensive search for cysteine cathepsins in the human genome.
  Biol Chem, 385, 363-372.  
14974080 C.Hewitt, D.McCormick, G.Linden, D.Turk, I.Stern, I.Wallace, L.Southern, L.Zhang, R.Howard, P.Bullon, M.Wong, R.Widmer, K.A.Gaffar, L.Awawdeh, J.Briggs, R.Yaghmai, E.W.Jabs, P.Hoeger, O.Bleck, S.G.Rüdiger, G.Petersilka, M.Battino, P.Brett, F.Hattab, M.Al-Hamed, P.Sloan, C.Toomes, M.Dixon, J.James, A.P.Read, and N.Thakker (2004).
The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis.
  Hum Mutat, 23, 222-228.  
15312091 C.Ullbro, B.Kinnby, P.Lindberg, and L.Matsson (2004).
Tissue plasminogen activator (t-PA) and placental plasminogen activator inhibitor (PAI-2) in gingival crevicular fluid from patients with Papillon-Lefèvre syndrome.
  J Clin Periodontol, 31, 708-712.  
15304495 M.Klemba, I.Gluzman, and D.E.Goldberg (2004).
A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation.
  J Biol Chem, 279, 43000-43007.  
12887049 B.Turk, H.Fritz, and V.Turk (2003).
Vito Turk--30 years of research on cysteine proteases and their inhibitors.
  Biol Chem, 384, 833-836.  
12887050 D.K.Nägler, and R.Ménard (2003).
Family C1 cysteine proteases: biological diversity or redundancy?
  Biol Chem, 384, 837-843.  
12554931 D.Turk, and G.Guncar (2003).
Lysosomal cysteine proteases (cathepsins): promising drug targets.
  Acta Crystallogr D Biol Crystallogr, 59, 203-213.  
14500882 M.Rzychon, R.Filipek, A.Sabat, K.Kosowska, A.Dubin, J.Potempa, and M.Bochtler (2003).
Staphostatins resemble lipocalins, not cystatins in fold.
  Protein Sci, 12, 2252-2256.
PDB code: 1nyc
14621998 O.Vasiljeva, M.Dolinar, V.Turk, and B.Turk (2003).
Recombinant human cathepsin H lacking the mini chain is an endopeptidase.
  Biochemistry, 42, 13522-13528.  
12437086 B.Turk, V.Stoka, J.Rozman-Pungercar, T.Cirman, G.Droga-Mazovec, K.Oresić, and V.Turk (2002).
Apoptotic pathways: involvement of lysosomal proteases.
  Biol Chem, 383, 1035-1044.  
12384499 C.Hink-Schauer, E.Estébanez-Perpiñá, E.Wilharm, P.Fuentes-Prior, W.Klinkert, W.Bode, and D.E.Jenne (2002).
The 2.2-A crystal structure of human pro-granzyme K reveals a rigid zymogen with unusual features.
  J Biol Chem, 277, 50923-50933.
PDB codes: 1mza 1mzd
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.