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PDBsum entry 2psa

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Kallikrein PDB id
2psa
Jmol
Contents
Protein chain
237 a.a.
Ligands
ACE-SER-SER-TYR-
TYR-SER-GLY-NH2
Theoretical model
PDB id:
2psa
Name: Kallikrein
Title: Knowledge based model of prostate specific antigen (theoretical model) bound to a consensus peptide substrate
Structure: Prostate specific antigen. Chain: a. Synonym: psa. Engineered: yes. Biological_unit: monomer. Consensus peptide substrate. Chain: i. Engineered: yes
Source: Homo sapiens. Human. Synthetic: yes. Other_details: hexapeptide
Authors: J.L.Pellequer
Key ref: G.S.Coombs et al. (1998). Substrate specificity of prostate-specific antigen (PSA). Chem Biol, 5, 475-488. PubMed id: 9751643
Date:
11-Mar-99     Release date:   16-Mar-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P07288  (KLK3_HUMAN) -  Prostate-specific antigen
Seq:
Struc:
261 a.a.
237 a.a.
Key:    PfamA domain  Secondary structure

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

 

 
Chem Biol 5:475-488 (1998)
PubMed id: 9751643  
 
 
Substrate specificity of prostate-specific antigen (PSA).
G.S.Coombs, R.C.Bergstrom, J.L.Pellequer, S.I.Baker, M.Navre, M.M.Smith, J.A.Tainer, E.L.Madison, D.R.Corey.
 
  ABSTRACT  
 
BACKGROUND: The serine protease prostate-specific antigen (PSA) is a useful clinical marker for prostatic malignancy. PSA is a member of the kallikrein subgroup of the (chymo)trypsin serine protease family, but differs from the prototypical member of this subgroup, tissue kallikrein, in possessing a specificity more similar to that of chymotrypsin than trypsin. We report the use of two strategies, substrate phage display and iterative optimization of natural cleavage sites, to identify labile sequences for PSA cleavage. RESULTS: Iterative optimization and substrate phage display converged on the amino-acid sequence SS(Y/F)Y decreases S(G/S) as preferred subsite occupancy for PSA. These sequences were cleaved by PSA with catalytic efficiencies as high as 2200-3100 M-1 s-1, compared with values of 2-46 M-1 s-1 for peptides containing likely physiological target sequences of PSA from the protein semenogelin. Substrate residues that bind to secondary (non-S1) subsites have a critical role in defining labile substrates and can even cause otherwise disfavored amino acids to bind in the primary specificity (S1) pocket. CONCLUSION: The importance of secondary subsites in defining both the specificity and efficiency of cleavage suggests that substrate recognition by PSA is mediated by an extended binding site. Elucidation of preferred subsite occupancy allowed refinement of the structural model of PSA and should facilitate the development of more sensitive activity-based assays and the design of potent inhibitors.
 

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.  
20180638 J.E.Swedberg, S.J.de Veer, and J.M.Harris (2010).
Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia.
  Biol Chem, 391, 357-374.  
19967419 M.Pakkala, J.Weisell, C.Hekim, J.Vepsäläinen, E.A.Wallen, U.H.Stenman, H.Koistinen, and A.Närvänen (2010).
Mimetics of the disulfide bridge between the N- and C-terminal cysteines of the KLK3-stimulating peptide B-2.
  Amino Acids, 39, 233-242.  
20615447 P.Goettig, V.Magdolen, and H.Brandstetter (2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
  Biochimie, 92, 1546-1567.  
20128688 P.Wu, J.Weisell, M.Pakkala, M.Peräkylä, L.Zhu, R.Koistinen, E.Koivunen, U.H.Stenman, A.Närvänen, and H.Koistinen (2010).
Identification of novel peptide inhibitors for human trypsins.
  Biol Chem, 391, 283-293.  
19377967 J.P.Hobson, S.Liu, S.H.Leppla, and T.H.Bugge (2009).
Imaging specific cell surface protease activity in living cells using reengineered bacterial cytotoxins.
  Methods Mol Biol, 539, 115-129.  
19705489 P.Singh, A.M.LeBeau, H.Lilja, S.R.Denmeade, and J.T.Isaacs (2009).
Molecular insights into substrate specificity of prostate specific antigen through structural modeling.
  Proteins, 77, 984-993.  
18627286 A.J.Ramsay, J.C.Reid, M.N.Adams, H.Samaratunga, Y.Dong, J.A.Clements, and J.D.Hooper (2008).
Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs).
  Biol Chem, 389, 653-668.  
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.  
18697857 H.Yoon, S.I.Blaber, D.M.Evans, J.Trim, M.A.Juliano, I.A.Scarisbrick, and M.Blaber (2008).
Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis.
  Protein Sci, 17, 1998-2007.  
18386289 J.M.Mattsson, L.Valmu, P.Laakkonen, U.H.Stenman, and H.Koistinen (2008).
Structural characterization and anti-angiogenic properties of prostate-specific antigen isoforms in seminal fluid.
  Prostate, 68, 945-954.  
17894328 P.Singh, S.A.Williams, M.H.Shah, T.Lectka, G.J.Pritchard, J.T.Isaacs, and S.R.Denmeade (2008).
Mechanistic insights into the inhibition of prostate specific antigen by beta-lactam class compounds.
  Proteins, 70, 1416-1428.  
17976015 C.A.Borgoño, J.A.Gavigan, J.Alves, B.Bowles, J.L.Harris, G.Sotiropoulou, and E.P.Diamandis (2007).
Defining the extended substrate specificity of kallikrein 1-related peptidases.
  Biol Chem, 388, 1215-1225.  
17828252 G.Blum, G.von Degenfeld, M.J.Merchant, H.M.Blau, and M.Bogyo (2007).
Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes.
  Nat Chem Biol, 3, 668-677.  
16799640 S.I.Hwang, J.Thumar, D.H.Lundgren, K.Rezaul, V.Mayya, L.Wu, J.Eng, M.E.Wright, and D.K.Han (2007).
Direct cancer tissue proteomics: a method to identify candidate cancer biomarkers from formalin-fixed paraffin-embedded archival tissues.
  Oncogene, 26, 65-76.  
16740631 M.Debela, V.Magdolen, N.Schechter, M.Valachova, F.Lottspeich, C.S.Craik, Y.Choe, W.Bode, and P.Goettig (2006).
Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences.
  J Biol Chem, 281, 25678-25688.  
16211657 F.Kratz, A.Mansour, J.Soltau, A.Warnecke, I.Fichtner, C.Unger, and J.Drevs (2005).
Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen.
  Arch Pharm (Weinheim), 338, 462-472.  
15895075 S.Liu, V.Redeye, J.G.Kuremsky, M.Kuhnen, A.Molinolo, T.H.Bugge, and S.H.Leppla (2005).
Intermolecular complementation achieves high-specificity tumor targeting by anthrax toxin.
  Nat Biotechnol, 23, 725-730.  
15516960 C.A.Borgoño, and E.P.Diamandis (2004).
The emerging roles of human tissue kallikreins in cancer.
  Nat Rev Cancer, 4, 876-890.  
12657647 H.R.Maun, C.Eigenbrot, and R.A.Lazarus (2003).
Engineering exosite peptides for complete inhibition of factor VIIa using a protease switch with substrate phage.
  J Biol Chem, 278, 21823-21830.  
12437093 D.Deperthes (2002).
Phage display substrate: a blind method for determining protease specificity.
  Biol Chem, 383, 1107-1112.  
11694539 E.I.Chen, S.J.Kridel, E.W.Howard, W.Li, A.Godzik, and J.W.Smith (2002).
A unique substrate recognition profile for matrix metalloproteinase-2.
  J Biol Chem, 277, 4485-4491.  
11784334 M.Brillard-Bourdet, S.Réhault, L.Juliano, M.Ferrer, T.Moreau, and F.Gauthier (2002).
Amidolytic activity of prostatic acid phosphatase on human semenogelins and semenogelin-derived synthetic substrates.
  Eur J Biochem, 269, 390-395.  
11863437 M.C.Hsieh, and B.S.Cooperman (2002).
Inhibition of prostate-specific antigen (PSA) by alpha(1)-antichymotrypsin: salt-dependent activation mediated by a conformational change.
  Biochemistry, 41, 2990-2997.  
11741926 N.A.Sharkov, and D.Cai (2002).
Discovery of substrate for type I signal peptidase SpsB from Staphylococcus aureus.
  J Biol Chem, 277, 5796-5803.  
12047384 S.M.Cloutier, J.R.Chagas, J.P.Mach, C.M.Gygi, H.J.Leisinger, and D.Deperthes (2002).
Substrate specificity of human kallikrein 2 (hK2) as determined by phage display technology.
  Eur J Biochem, 269, 2747-2754.  
11468412 A.L.Carvalho, J.M.Dias, L.Sanz, A.Romero, J.J.Calvete, and M.J.Romão (2001).
Purification, crystallization and identification by X-ray analysis of a prostate kallikrein from horse seminal plasma.
  Acta Crystallogr D Biol Crystallogr, 57, 1180-1183.  
11445898 P.Wang, D.F.Snavley, M.A.Freitas, and D.Pei (2001).
Screening combinatorial libraries for optimal enzyme substrates by mass spectrometry.
  Rapid Commun Mass Spectrom, 15, 1166-1171.  
11027412 J.Malm, J.Hellman, P.Hogg, and H.Lilja (2000).
Enzymatic action of prostate-specific antigen (PSA or hK3): substrate specificity and regulation by Zn(2+), a tight-binding inhibitor.
  Prostate, 45, 132-139.  
11012675 P.Wu, J.Leinonen, E.Koivunen, H.Lankinen, and U.H.Stenman (2000).
Identification of novel prostate-specific antigen-binding peptides modulating its enzyme activity.
  Eur J Biochem, 267, 6212-6220.  
10563510 C.F.Yang, E.S.Porter, J.Boths, D.Kanyi, M.Hsieh, and B.S.Cooperman (1999).
Design of synthetic hexapeptide substrates for prostate-specific antigen using single-position minilibraries.
  J Pept Res, 54, 444-448.  
10411640 J.Lövgren, K.Airas, and H.Lilja (1999).
Enzymatic action of human glandular kallikrein 2 (hK2). Substrate specificity and regulation by Zn2+ and extracellular protease inhibitors.
  Eur J Biochem, 262, 781-789.  
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.