PDBsum entry 1a7c

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Hydrolase inhibitor/peptide PDB id
Jmol PyMol
Protein chain
364 a.a. *
Waters ×69
* Residue conservation analysis
PDB id:
Name: Hydrolase inhibitor/peptide
Title: Human plasminogen activator inhibitor type-1 in complex with pentapeptide
Structure: Plasminogen activator inhibitor type 1. Chain: a. Synonym: pai-1. Engineered: yes. Mutation: yes. Pentapeptide. Chain: b, c. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho. Synthetic: yes
Biol. unit: Trimer (from PQS)
1.95Å     R-factor:   0.181     R-free:   0.210
Authors: Y.Xue,T.Inghardt,L.Sjolin,J.Deinum
Key ref:
Y.Xue et al. (1998). Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide. Structure, 6, 627-636. PubMed id: 9634700 DOI: 10.1016/S0969-2126(98)00064-1
12-Mar-98     Release date:   23-Mar-99    
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Protein chain
Pfam   ArchSchema ?
P05121  (PAI1_HUMAN) -  Plasminogen activator inhibitor 1
402 a.a.
364 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   6 terms 
  Biological process     positive regulation of leukotriene production involved in inflammatory response   30 terms 
  Biochemical function     protein binding     5 terms  


DOI no: 10.1016/S0969-2126(98)00064-1 Structure 6:627-636 (1998)
PubMed id: 9634700  
Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide.
Y.Xue, P.Björquist, T.Inghardt, M.Linschoten, D.Musil, L.Sjölin, J.Deinum.
BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is an important endogenous regulator of the fibrinolytic system. Reduction of PAI-1 activity has been shown to enhance dissolution of blood clots. Like other serpins, PAI-1 binds covalently to a target serine protease, thereby irreversibly inactivating the enzyme. During this process the exposed reactive-centre loop of PAI-1 is believed to undergo a conformational change becoming inserted into beta sheet A of the serpin. Incubation with peptides from the reactive-centre loop transform serpins into a substrate for their target protease. It has been hypothesised that these peptides bind to beta sheet A, thereby hindering the conformational rearrangement leading to loop insertion and formation of the stable serpin-protease complex. RESULTS: We report here the 1.95 A X-ray crystal structure of a complex of a glycosylated mutant of PAI-1, PAI-1-ala335Glu, with two molecules of the inhibitory reactive-centre loop peptide N-Ac-TVASS-NH2. Both bound peptide molecules are located between beta strands 3A and 5A of the serpin. The binding kinetics of the peptide inhibitor to immobilised PAI-1-Ala335Glu, as monitored by surface plasmon resonance, is consistent with there being two different binding sites. CONCLUSIONS: This is the first reported crystal structure of a complex formed between a serpin and a serpin inhibitor. The localisation of the inhibitory peptide in the complex strongly supports the theory that molecules binding in the space between beta strands 3A and 5A of a serpin are able to prevent insertion of the reactive-centre loop into beta sheet A, thereby abolishing the ability of the serpin to irreversibly inactivate its target enzyme. The characterisation of the two binding sites for the peptide inhibitor provides a solid foundation for computer-aided design of novel, low molecular weight PAI-1 inhibitors.
  Selected figure(s)  
Figure 1.
Figure 1. The structures of latent and active PAI-1. (a) Schematic model of latent PAI-1 [17] and (b) a constructed model of active PAI-1 [16] based on the structures of both latent PAI-1 and antithrombin III [38] with some important structural domains indicated. The protein is shown from the front with the b sheet A coloured red; b strands 3A to 5A are indicated. (The figure was prepared using the program MOLSCRIPT [39].)
  The above figure is reprinted by permission from Cell Press: Structure (1998, 6, 627-636) copyright 1998.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21136135 J.Schaller, and S.S.Gerber (2011).
The plasmin-antiplasmin system: structural and functional aspects.
  Cell Mol Life Sci, 68, 785-801.  
21280127 L.C.Thompson, S.Goswami, D.S.Ginsberg, D.E.Day, I.M.Verhamme, and C.B.Peterson (2011).
Metals affect the structure and activity of human plasminogen activator inhibitor-1. I. Modulation of stability and protease inhibition.
  Protein Sci, 20, 353-365.  
20731544 J.A.Huntington, and J.C.Whisstock (2010).
Molecular contortionism - on the physical limits of serpin 'loop-sheet' polymers.
  Biol Chem, 391, 973-982.  
19245336 B.Gooptu, and D.A.Lomas (2009).
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
  Annu Rev Biochem, 78, 147-176.  
19668868 C.W.Ko, Z.Wei, R.J.Marsh, D.A.Armoogum, N.Nicolaou, A.J.Bain, A.Zhou, and L.Ying (2009).
Probing nanosecond motions of plasminogen activator inhibitor-1 by time-resolved fluorescence anisotropy.
  Mol Biosyst, 5, 1025-1031.  
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.  
17018527 D.M.Dupont, G.E.Blouse, M.Hansen, L.Mathiasen, S.Kjelgaard, J.K.Jensen, A.Christensen, A.Gils, P.J.Declerck, P.A.Andreasen, and T.Wind (2006).
Evidence for a pre-latent form of the serpin plasminogen activator inhibitor-1 with a detached beta-strand 1C.
  J Biol Chem, 281, 36071-36081.  
16849336 K.J.Kinghorn, D.C.Crowther, L.K.Sharp, C.Nerelius, R.L.Davis, H.T.Chang, C.Green, D.C.Gubb, J.Johansson, and D.A.Lomas (2006).
Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease.
  J Biol Chem, 281, 29268-29277.  
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.  
14995992 K.Verbeke, A.Gils, and P.J.Declerck (2004).
Cloning and paratope analysis of an antibody fragment, a rational approach for the design of a PAI-1 inhibitor.
  J Thromb Haemost, 2, 289-297.  
12578831 A.Zhou, P.E.Stein, J.A.Huntington, and R.W.Carrell (2003).
Serpin polymerization is prevented by a hydrogen bond network that is centered on his-334 and stabilized by glycerol.
  J Biol Chem, 278, 15116-15122.
PDB code: 1lk6
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.  
12694180 J.S.Bødker, T.Wind, J.K.Jensen, M.Hansen, K.E.Pedersen, and P.A.Andreasen (2003).
Mapping of the epitope of a monoclonal antibody protecting plasminogen activator inhibitor-1 against inactivating agents.
  Eur J Biochem, 270, 1672-1679.  
11939796 J.A.Irving, R.N.Pike, W.Dai, D.Brömme, D.M.Worrall, G.A.Silverman, T.H.Coetzer, C.Dennison, S.P.Bottomley, and J.C.Whisstock (2002).
Evidence that serpin architecture intrinsically supports papain-like cysteine protease inhibition: engineering alpha(1)-antitrypsin to inhibit cathepsin proteases.
  Biochemistry, 41, 4998-5004.  
11821386 J.A.Irving, S.S.Shushanov, R.N.Pike, E.Y.Popova, D.Brömme, T.H.Coetzer, S.P.Bottomley, I.A.Boulynko, S.A.Grigoryev, and J.C.Whisstock (2002).
Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation.
  J Biol Chem, 277, 13192-13201.  
11741963 K.J.Belzar, A.Zhou, R.W.Carrell, P.G.Gettins, and J.A.Huntington (2002).
Helix D elongation and allosteric activation of antithrombin.
  J Biol Chem, 277, 8551-8558.  
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.  
11555638 D.N.Saunders, L.Jankova, S.J.Harrop, P.M.Curmi, A.R.Gould, M.Ranson, and M.S.Baker (2001).
Interaction between the P14 residue and strand 2 of beta-sheet B is critical for reactive center loop insertion in plasminogen activator inhibitor-2.
  J Biol Chem, 276, 43383-43389.  
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
10681574 D.A.Lawrence, S.T.Olson, S.Muhammad, D.E.Day, J.O.Kvassman, D.Ginsburg, and J.D.Shore (2000).
Partitioning of serpin-proteinase reactions between stable inhibition and substrate cleavage is regulated by the rate of serpin reactive center loop insertion into beta-sheet A.
  J Biol Chem, 275, 5839-5844.  
10368279 A.M.Sharp, P.E.Stein, N.S.Pannu, R.W.Carrell, M.B.Berkenpas, D.Ginsburg, D.A.Lawrence, and R.J.Read (1999).
The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion.
  Structure, 7, 111-118.
PDB code: 1b3k
10611648 D.G.Myszka (1999).
Survey of the 1998 optical biosensor literature.
  J Mol Recognit, 12, 390-408.  
10368272 S.J.Harrop, L.Jankova, M.Coles, D.Jardine, J.S.Whittaker, A.R.Gould, A.Meister, G.C.King, B.C.Mabbutt, and P.M.Curmi (1999).
The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function.
  Structure, 7, 43-54.
PDB code: 1by7
9914261 R.W.Carrell, and B.Gooptu (1998).
Conformational changes and disease--serpins, prions and Alzheimer's.
  Curr Opin Struct Biol, 8, 799-809.  
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.