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PDBsum entry 2zck
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Immune system PDB id
2zck

 

 

 

 

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Contents
Protein chains
237 a.a. *
218 a.a. *
230 a.a. *
Ligands
LYS-GLY-ILE-SER-
SER-GLN-TYR
NAG-MAN
Waters ×31
* Residue conservation analysis
PDB id:
2zck
Name: Immune system
Title: Crystal structure of a ternary complex between psa, a substrat-acyl intermediate and an activating antibody
Structure: Prostate-specific antigen. Chain: p. Fragment: unp residues 25-261. Synonym: psa, kallikrein- 3, semenogelase, gamma-seminoprotein, seminin, p-30 antigen. Kgissqy. Chain: s. Engineered: yes. Monoclonal antibody 8g8f5 fab.
Source: Homo sapiens. Human. Organism_taxid: 9606. Other_details: seminal fluids. Synthetic: yes. Other_details: peptide synthesis. Mus musculus. House mouse. Organism_taxid: 10090.
Resolution:
3.10Å     R-factor:   0.223     R-free:   0.275
Authors: R.Menez,E.Stura,C.Jolivet-Reynaud
Key ref:
R.Ménez et al. (2008). Crystal structure of a ternary complex between human prostate-specific antigen, its substrate acyl intermediate and an activating antibody. J Mol Biol, 376, 1021-1033. PubMed id: 18187150 DOI: 10.1016/j.jmb.2007.11.052
Date:
09-Nov-07     Release date:   29-Jan-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P07288  (KLK3_HUMAN) -  Prostate-specific antigen from Homo sapiens
Seq:
Struc: 		261 a.a.
237 a.a.
Protein chain
No UniProt id for this chain
Struc: 218 a.a.
Protein chain
No UniProt id for this chain
Struc: 230 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain P: E.C.3.4.21.77  - semenogelase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Tyr-|-Xaa.

 

 
DOI no: 10.1016/j.jmb.2007.11.052 J Mol Biol 376:1021-1033 (2008)
PubMed id: 18187150  
 
 
Crystal structure of a ternary complex between human prostate-specific antigen, its substrate acyl intermediate and an activating antibody.
R.Ménez, S.Michel, B.H.Muller, M.Bossus, F.Ducancel, C.Jolivet-Reynaud, E.A.Stura.
 
  ABSTRACT  
 
Human prostate-specific antigen (PSA or KLK3) is an important marker for the diagnosis and management of prostate cancer. This is an androgen-regulated glycoprotein of the kallikrein-related protease family secreted by prostatic epithelial cells. Its physiological function is to cleave semenogelins in the seminal coagulum and its enzymatic activity is strongly modulated by zinc ions. Here we present the first crystal structure of human PSA in complex with monoclonal antibody (mAb) 8G8F5 that enhances its enzymatic activity. The mAb recognizes an epitope composed of five discontinuous segments including residues from the kallikrein loop and stabilizes PSA in an "open and active conformation" that accelerates catalysis. We also present the crystal structure of PSA in complex with both the mAb 8G8F5 and a fluorogenic substrate Mu-KGISSQY-AFC, derived from semenogelin I. By exploiting the inhibition of PSA by zinc ions, we were able to obtain a substrate acyl intermediate covalently linked to the catalytic serine, at pH 7.3 but not at pH 5.5. Moreover, the inhibition of PSA activity by zinc was found to be modulated by pH variations but not by the antibody binding. The correlation of the different data with the physiological conditions under which PSA can cleave semenogelins is discussed.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Details of the Fab′ 8G8F5 epitope. (a) Interactions of PSA (pink) with 8G8F5 heavy chain (dark blue). (b) Interactions of PSA (pink) with 8G8F5 light chain (blue). 		Figure 5.
Fig. 5. Crystallographic dimer in PSA and HPK. (a) The dimer for PSA. The kallikrein loop is shown in dark green, the substrate in light green sticks and the carbohydrate moieties in CPK (beige and red). (b) PSA dimer (yellow and pink as in a) and crystal contacts with the antibody heavy chain (dark blue) showing the relationship between the substrate (CPK, light green) and the CH1 domain C-terminus bound by PSA (dark blue sticks). (c) The dimer for HPK.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 376, 1021-1033) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20180648 A.M.LeBeau, M.Kostova, C.S.Craik, and S.R.Denmeade (2010).
Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer.
  Biol Chem, 391, 333-343.  
20615447 P.Goettig, V.Magdolen, and H.Brandstetter (2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
  Biochimie, 92, 1546-1567.  
20704569 R.Ganesan, C.Eigenbrot, and D.Kirchhofer (2010).
Structural and mechanistic insight into how antibodies inhibit serine proteases.
  Biochem J, 430, 179-189.  
19196709 F.Cantini, D.Veggi, S.Dragonetti, S.Savino, M.Scarselli, G.Romagnoli, M.Pizza, L.Banci, and R.Rappuoli (2009).
Solution structure of the factor H-binding protein, a survival factor and protective antigen of Neisseria meningitidis.
  J Biol Chem, 284, 9022-9026.
PDB code: 2kc0
19819870 G.Sotiropoulou, G.Pampalakis, and E.P.Diamandis (2009).
Functional roles of human kallikrein-related peptidases.
  J Biol Chem, 284, 32989-32994.  
19128049 K.Y.White, L.Rodemich, J.O.Nyalwidhe, M.A.Comunale, M.A.Clements, R.S.Lance, P.F.Schellhammer, A.S.Mehta, O.J.Semmes, and R.R.Drake (2009).
Glycomic characterization of prostate-specific antigen and prostatic acid phosphatase in prostate cancer and benign disease seminal plasma fluids.
  J Proteome Res, 8, 620-630.  
19879144 Y.T.Aminetzach, J.R.Srouji, C.Y.Kong, and H.E.Hoekstra (2009).
Convergent evolution of novel protein function in shrew and lizard venom.
  Curr Biol, 19, 1925-1931.  
18635003 A.M.LeBeau, P.Singh, J.T.Isaacs, and S.R.Denmeade (2008).
Potent and selective peptidyl boronic acid inhibitors of the serine protease prostate-specific antigen.
  Chem Biol, 15, 665-674.  
18627344 H.Koistinen, A.Närvänen, M.Pakkala, C.Hekim, J.M.Mattsson, L.Zhu, P.Laakkonen, and U.H.Stenman (2008).
Development of peptides specifically modulating the activity of KLK2 and KLK3.
  Biol Chem, 389, 633-642.  
18500692 H.Koistinen, G.Wohlfahrt, J.M.Mattsson, P.Wu, J.Lahdenperä, and U.H.Stenman (2008).
Novel small molecule inhibitors for prostate-specific antigen.
  Prostate, 68, 1143-1151.  
18844454 J.A.Clements (2008).
Reflections on the tissue kallikrein and kallikrein-related peptidase family - from mice to men - what have we learnt in the last two decades?
  Biol Chem, 389, 1447-1454.  
18627343 M.Debela, N.Beaufort, V.Magdolen, N.M.Schechter, C.S.Craik, M.Schmitt, W.Bode, and P.Goettig (2008).
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7.
  Biol Chem, 389, 623-632.  
18817802 S.Liu, M.Z.Sun, C.Sun, B.Zhao, F.T.Greenaway, and Q.Zheng (2008).
A novel serine protease from the snake venom of Agkistrodon blomhoffii ussurensis.
  Toxicon, 52, 760-768.  
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.

 

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