PDBsum entry 1pfa

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Serine protease PDB id
Protein chain
237 a.a.
Theoretical model
PDB id:
Name: Serine protease
Structure: Prostate specific antigen (theoretical model)
Source: Human (homo sapiens)
Authors: B.O.Villoutreix,E.D.Getzoff,J.H.Griffin
Key ref:
B.O.Villoutreix et al. (1994). A structural model for the prostate disease marker, human prostate-specific antigen. Protein Sci, 3, 2033-2044. PubMed id: 7535613 DOI: 10.1002/pro.5560031116
08-Aug-94     Release date:   26-Jan-95    
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Protein chain
No UniProt id for this chain
Struc: 237 a.a.
Key:    Secondary structure


DOI no: 10.1002/pro.5560031116 Protein Sci 3:2033-2044 (1994)
PubMed id: 7535613  
A structural model for the prostate disease marker, human prostate-specific antigen.
B.O.Villoutreix, E.D.Getzoff, J.H.Griffin.
Prostate-specific antigen (PSA) provides an excellent serum marker for prostate cancer, the most frequent form of cancer in American males. PSA is a 237-residue protease based on sequence homology to kallikrein-like enzymes. To predict the 3-dimensional structure of PSA, homology modeling studies were performed based on sequence and structural alignments with tonin, pancreatic kallikrein, chymotrypsin, and trypsin. The structurally conserved regions of the 4 reference X-ray proteins provided the core structure of PSA, whereas the loop structures were modeled on the loops of tonin and kallikrein. The unique "kallikrein loop" insert, between Ser 95b and Pro 95k of kallikrein, was constructed using molecular mechanics, dynamics, and electrostatics calculations. In the resulting PSA structure, the catalytic triad, involving residues His 57, Asp 102, and Ser 195, and hydrophobic and electrostatic interactions typical of serine proteases were extremely well conserved. Similarly, the 5-disulfide bonds of kallikrein were also conserved in PSA. These results, together with the fact that no major steric clashes arose during the modeling process, provide strong evidence for the validity of the PSA model. Calculation of the electrostatic potential contours of kallikrein and PSA was carried out using the finite difference Poisson-Boltzmann method. The calculations revealed matching areas of negative potential near the catalytic triad, but differences in the positive potential surrounding the active site. The PSA glycosylation site, Asn 61, is fully accessible to the solvent and is enclosed in a positive region of the isopotential map. The bottom of the substrate specificity pocket, residue S1, is a serine (Ser 189) as in chymotrypsin, rather than aspartate (Asp 189) as in tonin, kallikrein, and trypsin. This fact, plus other features of the S1 binding-pocket region, suggest that PSA would prefer substrates with hydrophobic residues at the P1 position. The location of a potential zinc ion binding site involving the side chain of histidines 91, 101, and 233 is also suggested. This PSA model should facilitate the understanding and prediction of structural and functional properties of this important cancer marker.
  Selected figure(s)  
Figure 2.
ig. 2. Ramachandranplot of the minimizdPSAmodel structure. The hi and psiangles for thenon-glycineresidues are represntedascrosses and the glycineresidues are hownassquares.
Figure 4.
Fig. 4. Moleculardynamicssimulationofthekallikreinloopof PSA andverification of thestructures by heinverseprotein-foldingap- proach. A: Results of thedynamicssimulation of the PSA loopfrom residues 95 to 99. Solidribbonrepresentationof PA. The initialloop structure is shown in white. The catalytictriad residues arshon in pur- ple(Asp 102, His 57, andSer 195, from left to right). Theconforma- tionhavingthelowestpotentialenergystrucurefortheallikreinloop obtainedduringthedynamicsimulation is shown in blue.Thisstruc- ture fully coverstheactivesite.Thestructurewiththelowestsolvation energy is shown in red.This``open''coformationofthekallikreinloop of PSA allowsthedocking of a small eptidesubstrateintheactive site. Thisopenconformationwasconsideredmoresuitableforsubsequent structuralanalyses. B: Comparisonofthecalculated 3D profilesuing a10-residuewindow forthe model.Thex-axisdepictstheresidue umberandthe y-axisdepictsthe 3D score.Thehorizontalblackline epresentsthe value of hescore S, whereasthe verticalblacklines enclosetheloopatresidue 95. The lowest conformationalenergy(gray curve)andthelowestsolvationenergy(blackcurvecorrespondtothe dynamicssimulationsuperimposdexcept for heregion f theloopat residue 95. Thisgraphshowsthatthe PSA modelshave an cceptable verallconformation(positivescore)
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1994, 3, 2033-2044) copyright 1994.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21465221 Z.Kote-Jarai, A.Amin Al Olama, D.Leongamornlert, M.Tymrakiewicz, E.Saunders, M.Guy, G.G.Giles, G.Severi, M.Southey, J.L.Hopper, K.C.Sit, J.M.Harris, J.Batra, A.B.Spurdle, J.A.Clements, F.Hamdy, D.Neal, J.Donovan, K.Muir, P.D.Pharoah, S.J.Chanock, N.Brown, S.Benlloch, E.Castro, N.Mahmud, L.O'Brien, A.Hall, E.Sawyer, R.Wilkinson, D.F.Easton, and R.A.Eeles (2011).
Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.
  Hum Genet, 129, 687-694.  
20665692 A.Parracino, M.T.Neves-Petersen, A.K.di Gennaro, K.Pettersson, T.Lövgren, and S.B.Petersen (2010).
Arraying prostate specific antigen PSA and Fab anti-PSA using light-assisted molecular immobilization technology.
  Protein Sci, 19, 1751-1759.  
20615447 P.Goettig, V.Magdolen, and H.Brandstetter (2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
  Biochimie, 92, 1546-1567.  
  19241385 M.L.Zani, K.Baranger, N.Guyot, S.Dallet-Choisy, and T.Moreau (2009).
Protease inhibitors derived from elafin and SLPI and engineered to have enhanced specificity towards neutrophil serine proteases.
  Protein Sci, 18, 579-594.  
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.  
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.  
18083072 A.K.Satheesh Babu, M.A.Vijayalakshmi, G.J.Smith, and K.C.Chadha (2008).
Thiophilic-interaction chromatography of enzymatically active tissue prostate-specific antigen (T-PSA) and its modulation by zinc ions.
  J Chromatogr B Analyt Technol Biomed Life Sci, 861, 227-235.  
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.  
18519010 J.M.Levitt, and K.M.Slawin (2007).
Prostate-specific antigen and prostate-specific antigen derivatives as predictors of benign prostatic hyperplasia progression.
  Curr Urol Rep, 8, 269-274.  
17890654 M.I.Hassan, V.Kumar, R.K.Somvanshi, S.Dey, T.P.Singh, and S.Yadav (2007).
Structure-guided design of peptidic ligand for human prostate specific antigen.
  J Pept Sci, 13, 849-855.  
17718721 M.I.Hassan, V.Kumar, T.P.Singh, and S.Yadav (2007).
Structural model of human PSA: a target for prostate cancer therapy.
  Chem Biol Drug Des, 70, 261-267.  
16800733 T.Kishi, S.M.Cloutier, C.Kündig, D.Deperthes, and E.P.Diamandis (2006).
Activation and enzymatic characterization of recombinant human kallikrein 8.
  Biol Chem, 387, 723-731.  
15651049 G.Laxmikanthan, S.I.Blaber, M.J.Bernett, I.A.Scarisbrick, M.A.Juliano, and M.Blaber (2005).
1.70 A X-ray structure of human apo kallikrein 1: structural changes upon peptide inhibitor/substrate binding.
  Proteins, 58, 802-814.
PDB code: 1spj
15593306 S.Michel, E.Collomb-Clerc, C.Geourjon, J.P.Charrier, J.Passagot, Y.Courty, G.Deléage, and C.Jolivet-Reynaud (2005).
Selective recognition of enzymatically active prostate-specific antigen (PSA) by anti-PSA monoclonal antibodies.
  J Mol Recognit, 18, 225-235.  
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.  
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.  
11757074 S.Michel, E.Forest, Y.Pétillot, G.Deléage, N.Heuzé-Vourc'h, Y.Courty, D.Lascoux, M.Jolivet, and C.Jolivet-Reynaud (2001).
Involvement of the C-terminal end of the prostrate-specific antigen in a conformational epitope: characterization by proteolytic degradation of monoclonal antibody-bound antigen and mass spectrometry.
  J Mol Recognit, 14, 406-413.  
11074531 S.D.Mikolajczyk, L.S.Millar, K.M.Marker, T.J.Wang, H.G.Rittenhouse, L.S.Marks, and K.M.Slawin (2000).
Seminal plasma contains "BPSA," a molecular form of prostate-specific antigen that is associated with benign prostatic hyperplasia.
  Prostate, 45, 271-276.  
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.  
9751643 G.S.Coombs, R.C.Bergstrom, J.L.Pellequer, S.I.Baker, M.Navre, M.M.Smith, J.A.Tainer, E.L.Madison, and D.R.Corey (1998).
Substrate specificity of prostate-specific antigen (PSA).
  Chem Biol, 5, 475-488.
PDB code: 2psa
  9521101 T.Piironen, B.O.Villoutreix, C.Becker, K.Hollingsworth, M.Vihinen, D.Bridon, X.Qiu, J.Rapp, B.Dowell, T.Lövgren, K.Pettersson, and H.Lilja (1998).
Determination and analysis of antigenic epitopes of prostate specific antigen (PSA) and human glandular kallikrein 2 (hK2) using synthetic peptides and computer modeling.
  Protein Sci, 7, 259-269.  
  9232643 D.E.Timm (1997).
The crystal structure of the mouse glandular kallikrein-13 (prorenin converting enzyme).
  Protein Sci, 6, 1418-1425.
PDB code: 1ao5
9208936 S.D.Mikolajczyk, L.S.Millar, K.M.Marker, L.S.Grauer, A.Goel, M.M.Cass, A.Kumar, and M.S.Saedi (1997).
Ala217 is important for the catalytic function and autoactivation of prostate-specific human kallikrein 2.
  Eur J Biochem, 246, 440-446.  
  8732755 B.O.Villoutreix, H.Lilja, K.Pettersson, T.Lövgren, and O.Teleman (1996).
Structural investigation of the alpha-1-antichymotrypsin: prostate-specific antigen complex by comparative model building.
  Protein Sci, 5, 836-851.  
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.