PDBsum entry 1pca

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HydrolasE(C-terminal peptidase) PDB id
Protein chain
402 a.a. *
Waters ×294
* Residue conservation analysis
PDB id:
Name: HydrolasE(C-terminal peptidase)
Title: Three dimensional structure of porcine pancreatic procarboxypeptidase a. A comparison of the a and b zymogens and their determinants for inhibition and activation
Structure: Procarboxypeptidase a pcpa. Chain: a. Ec:
Source: Sus scrofa. Pig. Organism_taxid: 9823
2.00Å     R-factor:   not given    
Authors: A.Guasch,M.Coll,F.X.Aviles,R.Huber
Key ref: A.Guasch et al. (1992). Three-dimensional structure of porcine pancreatic procarboxypeptidase A. A comparison of the A and B zymogens and their determinants for inhibition and activation. J Mol Biol, 224, 141-157. PubMed id: 1548696
28-Oct-91     Release date:   31-Oct-93    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P09954  (CBPA1_PIG) -  Carboxypeptidase A1
419 a.a.
402 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 40 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Carboxypeptidase A.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidyl-L-amino acid + H2O = peptide + L-amino acid


Bound ligand (Het Group name = VAL)
matches with 55.00% similarity
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     hydrolase activity     7 terms  


    Added reference    
J Mol Biol 224:141-157 (1992)
PubMed id: 1548696  
Three-dimensional structure of porcine pancreatic procarboxypeptidase A. A comparison of the A and B zymogens and their determinants for inhibition and activation.
A.Guasch, M.Coll, F.X.Avilés, R.Huber.
The three-dimensional structure of procarboxypeptidase A (PCPA) from porcine pancreas has been determined at 2 A resolution and refined to a crystallographic R-factor of 0.198, with a root-mean-square deviation from ideal values for bond lengths of 0.015 A and for angles of 2.1 degrees. It is compared with procarboxypeptidase B (PCPB) from the same tissue. The 94/95 residue activation segments of PCPA/PCPB have equivalent folds: an N-terminal globular region with an open sandwich antiparallel alpha/antiparallel beta topology, followed by an extended alpha-helical segment, the connection to the enzyme. Alignment of the secondary structures of the activation segments of PCPA and PCPB (residues A1 to A99) indicates a two residue insertion between residues A34 and A35 and a C-terminal helix that is two turns longer in PCPA compared to PCPB. A deletion is observed between residues A43 to A45, the region containing the short 3(10) helix that covers the active site in PCPB. The globular region (A4 to A80) shields the preformed active center of carboxypeptidase A (CPA), but none of the residues involved in catalysis makes direct contacts with the activation segment. In contrast, subsites S2, S3 and S4 of the enzyme, involved in the binding of peptidic substrates, are blocked by specific contacts with residues AspA36, TrpA38, ArgA47, AspA53 and GluA86 of the activation segment. It has been described that several residues of CPA exhibit different conformations in the free enzyme compared to when substrate is bound: Arg127, Arg145, Glu270 and Tyr248. In PCPA all of these residues are found in the "active" conformation, as if substrate were actually bound. The presence of a ligand, tentatively interpreted as a free amino acid (Val) in the active center could explain this fact. The connecting region (A80 to A99), the target for proteolytic activation, establishes fewer contacts with the enzyme in PCPA than in PCPB. The activation segment of PCPA (A4 to A99) remains bound to the enzyme after the first trypsin cleavage between ArgA99-Ala1 probably due to the stability conferred on it by the alpha-helix (alpha 3) of the connecting segment. These and other structural features may explain the differences in intrinsic activity and different rates or proteolytic activation of each zymogen.

Literature references that cite this PDB file's key reference

  PubMed id Reference
18566513 I.Pallarès, D.Fernández, M.Comellas-Bigler, J.Fernández-Recio, S.Ventura, F.X.Avilés, W.Bode, and J.Vendrell (2008).
Direct interaction between a human digestive protease and the mucoadhesive poly(acrylic acid).
  Acta Crystallogr D Biol Crystallogr, 64, 784-791.
PDB code: 2v77
17511606 V.K.h.Akparov, A.M.Grishin, M.P.Yusupova, N.M.Ivanova, and G.G.Chestukhina (2007).
Structural principles of the wide substrate specificity of Thermoactinomyces vulgaris carboxypeptidase T. Reconstruction of the carboxypeptidase B primary specificity pocket.
  Biochemistry (Mosc), 72, 416-423.  
16260742 A.Bayés, M.Comellas-Bigler, M.Rodríguez de la Vega, K.Maskos, W.Bode, F.X.Aviles, M.A.Jongsma, J.Beekwilder, and J.Vendrell (2005).
Structural basis of the resistance of an insect carboxypeptidase to plant protease inhibitors.
  Proc Natl Acad Sci U S A, 102, 16602-16607.
PDB code: 2c1c
15738388 I.Pallarès, R.Bonet, R.García-Castellanos, S.Ventura, F.X.Avilés, J.Vendrell, and F.X.Gomis-Rüth (2005).
Structure of human carboxypeptidase A4 with its endogenous protein inhibitor, latexin.
  Proc Natl Acad Sci U S A, 102, 3978-3983.
PDB codes: 2bk7 2bo9
15561703 J.L.Arolas, J.Lorenzo, A.Rovira, J.Castellà, F.X.Aviles, and C.P.Sommerhoff (2005).
A carboxypeptidase inhibitor from the tick Rhipicephalus bursa: isolation, cDNA cloning, recombinant expression, and characterization.
  J Biol Chem, 280, 3441-3448.  
12538893 M.A.Jiménez, V.Villegas, J.Santoro, L.Serrano, J.Vendrell, F.X.Avilés, and M.Rico (2003).
NMR solution structure of the activation domain of human procarboxypeptidase A2.
  Protein Sci, 12, 296-305.
PDB code: 1o6x
14500874 R.Gargallo, P.H.Hünenberger, F.X.Avilés, and B.Oliva (2003).
Molecular dynamics simulation of highly charged proteins: comparison of the particle-particle particle-mesh and reaction field methods for the calculation of electrostatic interactions.
  Protein Sci, 12, 2161-2172.  
  11836249 S.Wei, S.Segura, J.Vendrell, F.X.Aviles, E.Lanoue, R.Day, Y.Feng, and L.D.Fricker (2002).
Identification and characterization of three members of the human metallocarboxypeptidase gene family.
  J Biol Chem, 277, 14954-14964.  
  11274481 H.Neurath, and H.Neurath (2001).
From proteases to proteomics.
  Protein Sci, 10, 892-904.  
10715106 S.Bhattacharjya, P.Xu, M.Zhong, M.Chrétien, N.G.Seidah, and F.Ni (2000).
Inhibitory activity and structural characterization of a C-terminal peptide fragment derived from the prosegment of the proprotein convertase PC7.
  Biochemistry, 39, 2868-2877.  
10022548 D.A.Hamstra, and A.Rehemtulla (1999).
Toward an enzyme/prodrug strategy for cancer gene therapy: endogenous activation of carboxypeptidase A mutants by the PACE/Furin family of propeptidases.
  Hum Gene Ther, 10, 235-248.  
10545093 F.X.Gomis-Rüth, V.Companys, Y.Qian, L.D.Fricker, J.Vendrell, F.X.Avilés, and M.Coll (1999).
Crystal structure of avian carboxypeptidase D domain II: a prototype for the regulatory metallocarboxypeptidase subfamily.
  EMBO J, 18, 5817-5826.
PDB code: 1qmu
10022823 H.Jing, K.J.Macon, D.Moore, L.J.DeLucas, J.E.Volanakis, and S.V.Narayana (1999).
Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.
  EMBO J, 18, 804-814.
PDB code: 1fdp
10092856 S.Darnis, N.Juge, C.Marino, F.X.Avilés, A.Puigserver, J.C.Chaix, and X.J.Guo (1999).
Cloning, sequencing and functional expression of a cDNA encoding porcine pancreatic preprocarboxypeptidase A1.
  Eur J Biochem, 259, 719-725.  
10391940 S.Ventura, V.Villegas, J.Sterner, J.Larson, J.Vendrell, C.L.Hershberger, and F.X.Avilés (1999).
Mapping the pro-region of carboxypeptidase B by protein engineering. Cloning, overexpression, and mutagenesis of the porcine proenzyme.
  J Biol Chem, 274, 19925-19933.  
9846867 D.Baker (1998).
Metastable states and folding free energy barriers.
  Nat Struct Biol, 5, 1021-1024.  
9830043 D.Reverter, J.Vendrell, F.Canals, J.Horstmann, F.X.Avilés, H.Fritz, and C.P.Sommerhoff (1998).
A carboxypeptidase inhibitor from the medical leech Hirudo medicinalis. Isolation, sequence analysis, cDNA cloning, recombinant expression, and characterization.
  J Biol Chem, 273, 32927-32933.  
9452479 D.Reverter, S.Ventura, V.Villegas, J.Vendrell, and F.X.Avilés (1998).
Overexpression of human procarboxypeptidase A2 in Pichia pastoris and detailed characterization of its activation pathway.
  J Biol Chem, 273, 3535-3541.  
  9524066 P.Aloy, L.Catasús, V.Villegas, D.Reverter, J.Vendrell, and F.X.Avilés (1998).
Comparative analysis of the sequences and three-dimensional models of human procarboxypeptidases A1, A2 and B.
  Biol Chem, 379, 149-155.  
9188741 A.V.Efimov (1997).
Structural trees for protein superfamilies.
  Proteins, 28, 241-260.  
9384570 I.García-Sáez, D.Reverter, J.Vendrell, F.X.Avilés, and M.Coll (1997).
The three-dimensional structure of human procarboxypeptidase A2. Deciphering the basis of the inhibition, activation and intrinsic activity of the zymogen.
  EMBO J, 16, 6906-6913.
PDB code: 1aye
9030763 M.Bruix, V.Muñoz, R.Campos-Olivas, J.R.Del Bosque, L.Serrano, and M.Rico (1997).
Characterisation of the isolated Che Y C-terminal fragment (79-129)--Exploring the structure/stability/folding relationship of the alpha/beta parallel protein Che Y.
  Eur J Biochem, 243, 384-392.  
9083113 S.Rowsell, R.A.Pauptit, A.D.Tucker, R.G.Melton, D.M.Blow, and P.Brick (1997).
Crystal structure of carboxypeptidase G2, a bacterial enzyme with applications in cancer therapy.
  Structure, 5, 337-347.
PDB code: 1cg2
  9165062 W.Baumeister, Z.Cejka, M.Kania, and E.Seemüller (1997).
The proteasome: a macromolecular assembly designed to confine proteolysis to a nanocompartment.
  Biol Chem, 378, 121-130.  
8740363 M.Cygler, J.Sivaraman, P.Grochulski, R.Coulombe, A.C.Storer, and J.S.Mort (1996).
Structure of rat procathepsin B: model for inhibition of cysteine protease activity by the proregion.
  Structure, 4, 405-416.
PDB code: 1mir
8799115 R.Huber, P.Hof, R.O.Duarte, J.J.Moura, I.Moura, M.Y.Liu, J.LeGall, R.Hille, M.Archer, and M.J.Romão (1996).
A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes.
  Proc Natl Acad Sci U S A, 93, 8846-8851.  
7836395 E.B.Springman, M.M.Dikov, and W.E.Serafin (1995).
Mast cell procarboxypeptidase A. Molecular modeling and biochemical characterization of its processing within secretory granules.
  J Biol Chem, 270, 1300-1307.  
8618874 E.Normant, M.P.Martres, J.C.Schwartz, and C.Gros (1995).
Purification, cDNA cloning, functional expression, and characterization of a 26-kDa endogenous mammalian carboxypeptidase inhibitor.
  Proc Natl Acad Sci U S A, 92, 12225-12229.  
  7556081 F.X.Gomis-Rüth, M.Gómez, W.Bode, R.Huber, and F.X.Avilés (1995).
The three-dimensional structure of the native ternary complex of bovine pancreatic procarboxypeptidase A with proproteinase E and chymotrypsinogen C.
  EMBO J, 14, 4387-4394.
PDB code: 1pyt
8591035 G.Rudenko, E.Bonten, A.d'Azzo, and W.G.Hol (1995).
Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism.
  Structure, 3, 1249-1259.
PDB code: 1ivy
8535784 T.Gallagher, G.Gilliland, L.Wang, and P.Bryan (1995).
The prosegment-subtilisin BPN' complex: crystal structure of a specific 'foldase'.
  Structure, 3, 907-914.
PDB code: 1spb
  8528077 V.Villegas, J.Vendrell, and X.Avilés (1995).
The activation pathway of procarboxypeptidase B from porcine pancreas: participation of the active enzyme in the proteolytic processing.
  Protein Sci, 4, 1792-1800.  
8200353 O.Oppezzo, S.Ventura, T.Bergman, J.Vendrell, H.Jörnvall, and F.X.Avilés (1994).
Procarboxypeptidase in rat pancreas. Overall characterization and comparison of the activation processes.
  Eur J Biochem, 222, 55-63.  
8436102 F.X.Avilés, J.Vendrell, A.Guasch, M.Coll, and R.Huber (1993).
Advances in metallo-procarboxypeptidases. Emerging details on the inhibition mechanism and on the activation process.
  Eur J Biochem, 211, 381-389.  
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.