PDBsum entry 1db2

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Hydrolase inhibitor PDB id
Protein chain
377 a.a. *
* Residue conservation analysis
PDB id:
Name: Hydrolase inhibitor
Title: Crystal structure of native plasminogen activator inhibitor- 1
Structure: Plasminogen activator inhibitor-1. Chain: a, b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
2.70Å     R-factor:   0.255     R-free:   0.299
Authors: H.Nar,M.Bauer,J.M.Stassen,D.Lang,A.Gils,P.Declerck
Key ref:
H.Nar et al. (2000). Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivation. J Mol Biol, 297, 683-695. PubMed id: 10731421 DOI: 10.1006/jmbi.2000.3604
02-Nov-99     Release date:   10-Nov-99    
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Protein chains
Pfam   ArchSchema ?
P05121  (PAI1_HUMAN) -  Plasminogen activator inhibitor 1
402 a.a.
377 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   5 terms 
  Biological process     positive regulation of leukotriene production involved in inflammatory response   37 terms 
  Biochemical function     protein binding     5 terms  


DOI no: 10.1006/jmbi.2000.3604 J Mol Biol 297:683-695 (2000)
PubMed id: 10731421  
Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivation.
H.Nar, M.Bauer, J.M.Stassen, D.Lang, A.Gils, P.J.Declerck.
The crystal structure of a constitutively active multiple site mutant of plasminogen activator inhibitor 1 (PAI-1) was determined and refined at a resolution of 2.7 A.The present structure comprises a dimer of two crystallographically independent PAI-1 molecules that pack by association of the residues P6 to P3 of the reactive centre loop of one molecule (A) with the edge of the main beta-sheet A of the other molecule (B).Thus, the reactive centre loop is ordered for molecule A by crystal packing forces, while for molecule B it is unconstrained by crystal packing contacts and is disordered.The overall structure of active PAI-1 is similar to the structures of other active inhibitory serpins exhibiting as the major secondary structural feature a five-stranded beta-sheet A and an intact proteinase-binding loop protruding from the one end of the elongated molecule. No preinsertion of the reactive centre loop is observed in this structure.A comparison of the present structure with the previously determined crystal structures of PAI-1 in its alternative conformations reveals that, upon cleavage of an intact form of PAI-1 or formation of latent PAI-1, the well-characterised rearrangements of the serpin secondary structural elements are accompanied by dramatic and partly unexpected conformational changes of helical and loop structures proximal to beta-sheet A.The present structure explains the stabilising effects of the mutated residues, reveals the structural cause for the observed spectroscopic differences between active and latent PAI-1, and provides new insights into possible mechanisms of stabilisation by its natural binding partner, vitronectin.
  Selected figure(s)  
Figure 7.
Figure 7. Stereo representation of the hD-s2A loop region in active PAI-1 (blue) superimposed on the loop structure of the peptide-bound form of PAI-1 (magenta). The loop adopts a totally new conformation. The C-terminal end of hD is located further to the left, compromising the new position of s2A in the closed sheet A. W86 apparently is expelled from a partially buried position behind hD in active PAI-1 to a fully external position in latent, cleaved or peptide bound PAI-1. s2A is shorter by two residues in active PAI-1 due to the loop rearrangement. The hydrogen bond between N89 and H229 in the other PAI-1 conformers is replaced by a hydrogen bond between E90 and H229.
Figure 9.
Figure 9. Surface representation of Figure 8 showing the cavity formed in intact PAI-1 at the edge of sheet A between helices D, E and strands s1A and s2A.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 297, 683-695) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21280128 L.C.Thompson, S.Goswami, and C.B.Peterson (2011).
Metals affect the structure and activity of human plasminogen activator inhibitor-1. II. Binding affinity and conformational changes.
  Protein Sci, 20, 366-378.  
21081089 S.Ricagno, M.Pezzullo, A.Barbiroli, M.Manno, M.Levantino, M.G.Santangelo, F.Bonomi, and M.Bolognesi (2010).
Two latent and two hyperstable polymeric forms of human neuroserpin.
  Biophys J, 99, 3402-3411.  
19017261 D.C.Rijken, and H.R.Lijnen (2009).
New insights into the molecular mechanisms of the fibrinolytic system.
  J Thromb Haemost, 7, 4.  
18658131 C.R.Schar, J.K.Jensen, A.Christensen, G.E.Blouse, P.A.Andreasen, and C.B.Peterson (2008).
Characterization of a Site on PAI-1 That Binds to Vitronectin Outside of the Somatomedin B Domain.
  J Biol Chem, 283, 28487-28496.  
18725454 J.K.Jensen, and P.G.Gettins (2008).
High-resolution structure of the stable plasminogen activator inhibitor type-1 variant 14-1B in its proteinase-cleaved form: a new tool for detailed interaction studies and modeling.
  Protein Sci, 17, 1844-1849.
PDB code: 3cvm
18436534 S.H.Li, N.V.Gorlatova, D.A.Lawrence, and B.S.Schwartz (2008).
Structural differences between active forms of plasminogen activator inhibitor type 1 revealed by conformationally sensitive ligands.
  J Biol Chem, 283, 18147-18157.  
19000814 X.Luo, and H.Yu (2008).
Protein metamorphosis: the two-state behavior of Mad2.
  Structure, 16, 1616-1625.  
17613529 A.A.Komissarov, A.Zhou, and P.J.Declerck (2007).
Modulation of serpin reaction through stabilization of transient intermediate by ligands bound to alpha-helix F.
  J Biol Chem, 282, 26306-26315.  
17635716 J.C.Rau, L.M.Beaulieu, J.A.Huntington, and F.C.Church (2007).
Serpins in thrombosis, hemostasis and fibrinolysis.
  J Thromb Haemost, 5, 102-115.  
15653733 C.Boudier, A.Gils, P.J.Declerck, and J.G.Bieth (2005).
The conversion of active to latent plasminogen activator inhibitor-1 is an energetically silent event.
  Biophys J, 88, 2848-2854.  
14988411 B.De Taeye, G.Compernolle, and P.J.Declerck (2004).
Site-directed targeting of plasminogen activator inhibitor-1 as an example for a novel approach in rational drug design.
  J Biol Chem, 279, 20447-20450.  
15337743 B.N.Nukuna, M.S.Penn, V.E.Anderson, and S.L.Hazen (2004).
Latency and substrate binding globally reduce solvent accessibility of plasminogen activator inhibitor type 1 (PAI-1). An adaptation of PAI-1 conformer crystal structures by hydrogen-deuterium exchange.
  J Biol Chem, 279, 50132-50141.  
15095413 Y.Chen, R.J.Kelm, R.C.Budd, B.E.Sobel, and D.J.Schneider (2004).
Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1.
  J Cell Biochem, 92, 178-188.  
12686544 B.De Taeye, G.Compernolle, M.Dewilde, W.Biesemans, and P.J.Declerck (2003).
Immobilization of the distal hinge in the labile serpin plasminogen activator inhibitor 1: identification of a transition state with distinct conformational and functional properties.
  J Biol Chem, 278, 23899-23905.  
12871373 D.Naessens, A.Gils, G.Compernolle, and P.J.Declerck (2003).
Elucidation of a novel epitope of a substrate-inducing monoclonal antibody against the serpin PAI-1.
  J Thromb Haemost, 1, 1028-1033.  
12829505 S.Verheyden, A.Sillen, A.Gils, P.J.Declerck, and Y.Engelborghs (2003).
Tryptophan properties in fluorescence and functional stability of plasminogen activator inhibitor 1.
  Biophys J, 85, 501-510.  
12694181 T.Wind, J.K.Jensen, D.M.Dupont, P.Kulig, and P.A.Andreasen (2003).
Mutational analysis of plasminogen activator inhibitor-1.
  Eur J Biochem, 270, 1680-1688.  
12223472 A.A.Komissarov, P.J.Declerck, and J.D.Shore (2002).
Mechanisms of conversion of plasminogen activator inhibitor 1 from a suicide inhibitor to a substrate by monoclonal antibodies.
  J Biol Chem, 277, 43858-43865.  
11928815 T.Wind, M.Hansen, J.K.Jensen, and P.A.Andreasen (2002).
The molecular basis for anti-proteolytic and non-proteolytic functions of plasminogen activator inhibitor type-1: roles of the reactive centre loop, the shutter region, the flexible joint region and the small serpin fragment.
  Biol Chem, 383, 21-36.  
11546761 L.Jankova, S.J.Harrop, D.N.Saunders, J.L.Andrews, K.C.Bertram, A.R.Gould, M.S.Baker, and P.M.Curmi (2001).
Crystal structure of the complex of plasminogen activator inhibitor 2 with a peptide mimicking the reactive center loop.
  J Biol Chem, 276, 43374-43382.
PDB code: 1jrr
11733024 M.Hansen, M.N.Busse, and P.A.Andreasen (2001).
Importance of the amino-acid composition of the shutter region of plasminogen activator inhibitor-1 for its transitions to latent and substrate forms.
  Eur J Biochem, 268, 6274-6283.  
11274471 P.Krüger, S.Verheyden, P.J.Declerck, and Y.Engelborghs (2001).
Extending the capabilities of targeted molecular dynamics: simulation of a large conformational transition in plasminogen activator inhibitor 1.
  Protein Sci, 10, 798-808.  
12540280 S.Rosenberg (2001).
New developments in the urokinase-type plasminogen activator system.
  Expert Opin Ther Targets, 5, 711-722.  
11179976 T.Wind, M.A.Jensen, and P.A.Andreasen (2001).
Epitope mapping for four monoclonal antibodies against human plasminogen activator inhibitor type-1: implications for antibody-mediated PAI-1-neutralization and vitronectin-binding.
  Eur J Biochem, 268, 1095-1106.  
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.