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PDBsum entry 8cpa

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protein ligands metals links
HydrolasE(C-terminal peptidase) PDB id
8cpa
Jmol
Contents
Protein chain
307 a.a. *
Ligands
AGF
Metals
_ZN
Waters ×254
* Residue conservation analysis
PDB id:
8cpa
Name: HydrolasE(C-terminal peptidase)
Title: Comparison of the structures of three carboxypeptidase a- phosphonate complexes determined by x-ray crystallography
Structure: Carboxypeptidase a. Chain: a. Engineered: yes
Source: Bos taurus. Cattle. Organism_taxid: 9913
Resolution:
2.00Å     R-factor:   0.186    
Authors: H.Kim,W.N.Lipscomb
Key ref:
H.Kim and W.N.Lipscomb (1991). Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography. Biochemistry, 30, 8171-8180. PubMed id: 1868092 DOI: 10.1021/bi00247a012
Date:
21-May-91     Release date:   31-Jan-94    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00730  (CBPA1_BOVIN) -  Carboxypeptidase A1
Seq:
Struc:
419 a.a.
307 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 9 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.17.1  - Carboxypeptidase A.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidyl-L-amino acid + H2O = peptide + L-amino acid

+
=
+
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     zinc ion binding     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/bi00247a012 Biochemistry 30:8171-8180 (1991)
PubMed id: 1868092  
 
 
Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography.
H.Kim, W.N.Lipscomb.
 
  ABSTRACT  
 
The structures of the complexes of carboxypeptidase A (CPA) with two tight-binding phosphonate inhibitors have been determined by X-ray crystallography. The inhibitors, Cbz-Phe-ValP-(O)-Phe[ZFVP(O)F] and Cbz-Ala-GlyP-(O)-Phe[ZAGP(O)F], bind noncovalently to CPA with dissociation constants (Ki's) of 11 fM and 710 pM, respectively. The CPA-ZFVP(O)F complex crystallizes in the space group P2(1)2(1)2(1) with unit cell parameters a = 65.3 A, b = 63.4 A, and c = 76.0 A, and the CPA-ZAGP(O)F complex crystallizes in the space group P2(1)2(1)2(1) with unit cell parameters a = 63.4 A, b = 65.9 A, and c = 74.4 A. Both structures were determined by molecular replacement to a resolution of 2.0 A. The final crystallographic residuals are 0.189 for the CPA-ZFVP(O)F complex and 0.191 for the CPA-ZAGP(O)F complex. The CPA-ZFVP(O)F complex exhibits the lowest Ki yet determined for an enzyme-inhibitor interaction. Comparison of the CPA-ZFVP(O)F structure with that of the CPA-ZAAP(O)F complex [Kim, H., & Lipscomb, W.N. (1990) Biochemistry 29, 5546-5555] indicates the likely important contributions of hydrophobic and weakly polar enzyme-inhibitor interactions to the exceptional stability of the CPA-ZFVP(O)F complex. Among these interactions is a network of four aromatic rings of CPA and ZFVP(O)F in a configuration that allows stabilizing aromatic-aromatic edge-to-face interactions from one ring to the next. A comparison of the structures of the CPA-ZFVP(O)F, CPA-ZAAP(O)F and CPA-ZAGP(O)F complexes shows that all three phosphonates assume a similar binding mode in the active-site binding groove of CPA. For ZAGP(O)F, the glycyl P1 residue does not lead to an anomalous or a partially disordered binding mode as seen in some previous complexes of CPA involving dipeptide analogue inhibitors with glycyl P1 residues. The additional enzyme-inhibitor interactions for these tripeptide phosphonates secure a binding mode in which a Pi portion of the inhibitor is clearly bound by the corresponding Si binding subsite. These three phosphonates have been implicated as transition-state analogues of the CPA-catalyzed reaction. The phosphinyl groups of these phosphonates coordinate to the active-site zinc in a manner that has been proposed as a characteristic feature of the general-base (Zn-hydroxyl or Zn-water) mechanism for the CPA-catalyzed reaction. Further mechanistic proposals are made for Arg-127, whose probable role in binding substrates is apparent in these CPA-phosphonate complexes.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19640844 X.Deng, R.Gujjar, F.El Mazouni, W.Kaminsky, N.A.Malmquist, E.J.Goldsmith, P.K.Rathod, and M.A.Phillips (2009).
Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds.
  J Biol Chem, 284, 26999-27009.
PDB codes: 3i65 3i68 3i6r
18991561 A.M.Grishin, V.K.h.Akparov, and G.G.Chestukhina (2008).
Leu254 residue and calcium ions as new structural determinants of carboxypeptidase T substrate specificity.
  Biochemistry (Mosc), 73, 1140-1145.  
18041759 B.Seebeck, I.Reulecke, A.Kämper, and M.Rarey (2008).
Modeling of metal interaction geometries for protein-ligand docking.
  Proteins, 71, 1237-1254.  
18219114 M.Adler, B.Buckman, J.Bryant, Z.Chang, K.Chu, K.Emayan, P.Hrvatin, I.Islam, J.Morser, D.Sukovich, C.West, S.Yuan, and M.Whitlow (2008).
Structures of potent selective peptide mimetics bound to carboxypeptidase B.
  Acta Crystallogr D Biol Crystallogr, 64, 149-157.
PDB codes: 2piy 2piz 2pj0 2pj1 2pj2 2pj3 2pj4 2pj5 2pj6 2pj7 2pj8 2pj9 2pja 2pjb 2pjc
17391648 J.R.Hershfield, N.Pattabiraman, C.N.Madhavarao, and M.A.Namboodiri (2007).
Mutational analysis of aspartoacylase: implications for Canavan disease.
  Brain Res, 1148, 1.  
15027050 S.Swaminathan, S.Eswaramoorthy, and D.Kumaran (2004).
Structure and enzymatic activity of botulinum neurotoxins.
  Mov Disord, 19, S17-S22.  
12554943 A.Kilshtain-Vardi, M.Glick, H.M.Greenblatt, A.Goldblum, and G.Shoham (2003).
Refined structure of bovine carboxypeptidase A at 1.25 A resolution.
  Acta Crystallogr D Biol Crystallogr, 59, 323-333.
PDB code: 1m4l
11679714 K.Harata, W.D.Schubert, and M.Muraki (2001).
Structure of Urtica dioica agglutinin isolectin I: dimer formation mediated by two zinc ions bound at the sugar-binding site.
  Acta Crystallogr D Biol Crystallogr, 57, 1513-1517.
PDB code: 1iqb
10955996 D.M.van Aalten, C.R.Chong, and L.Joshua-Tor (2000).
Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 A - inhibitor-induced conformational changes.
  Biochemistry, 39, 10082-10089.
PDB code: 1f57
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
  9568890 A.R.Khan, and M.N.James (1998).
Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes.
  Protein Sci, 7, 815-836.  
9348662 C.L.Perrin, and J.B.Nielson (1997).
"Strong" hydrogen bonds in chemistry and biology.
  Annu Rev Phys Chem, 48, 511-544.  
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
9228942 Z.Wang, H.Luecke, N.Yao, and F.A.Quiocho (1997).
A low energy short hydrogen bond in very high resolution structures of protein receptor--phosphate complexes.
  Nat Struct Biol, 4, 519-522.
PDB codes: 1ixg 1ixh 1ixi
8807874 G.MacBeath, and D.Hilvert (1996).
Hydrolytic antibodies: variations on a theme.
  Chem Biol, 3, 433-445.  
7711255 H.Zhang, and R.G.Bryant (1995).
Characterization of enzyme-bound ligand dynamics by solid-state NMR in the presence of ligand exchange: L-phenylalanine on carboxypeptidase A.
  Biophys J, 68, 303-311.  
7964925 H.J.Böhm (1994).
The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure.
  J Comput Aided Mol Des, 8, 243-256.  
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.  
1521526 A.Teplyakov, K.Polyakov, G.Obmolova, B.Strokopytov, I.Kuranova, A.Osterman, N.Grishin, S.Smulevitch, O.Zagnitko, and O.Galperina (1992).
Crystal structure of carboxypeptidase T from Thermoactinomyces vulgaris.
  Eur J Biochem, 208, 281-288.
PDB code: 1obr
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.