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PDBsum entry 2arq

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protein Protein-protein interface(s) links
Hydrolase inhibitor/peptide PDB id
2arq
Jmol
Contents
Protein chains
360 a.a. *
15 a.a. *
Waters ×345
* Residue conservation analysis
PDB id:
2arq
Name: Hydrolase inhibitor/peptide
Title: Human plasminogen activator inhibitor-2.[Loop (66-98) deleti complexed with peptide n-acetyl-teaaagdggvmtgr-oh
Structure: Plasminogen activator inhibitor-2. Chain: a. Synonym: pai-2, placental plasminogen activator inhibitor, arg-serpin, urokinase inhibitor. Engineered: yes. 14-mer from plasminogen activator inhibitor-2. Chain: p. Synonym: pai-2, placental plasminogen activator inhibitor, arg-serpin, urokinase inhibitor.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
1.85Å     R-factor:   0.185     R-free:   0.248
Authors: D.A.Di Giusto,A.P.Sutherland,L.Jankova,S.J.Harrop,P.M.Curmi,
Key ref:
D.A.Di Giusto et al. (2005). Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities. J Mol Biol, 353, 1069-1080. PubMed id: 16214170 DOI: 10.1016/j.jmb.2005.09.008
Date:
21-Aug-05     Release date:   11-Jul-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P05120  (PAI2_HUMAN) -  Plasminogen activator inhibitor 2
Seq:
Struc:
415 a.a.
360 a.a.*
Protein chain
Pfam   ArchSchema ?
P05120  (PAI2_HUMAN) -  Plasminogen activator inhibitor 2
Seq:
Struc:
415 a.a.
14 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   4 terms 
  Biological process     wound healing   7 terms 
  Biochemical function     peptidase inhibitor activity     2 terms  

 

 
DOI no: 10.1016/j.jmb.2005.09.008 J Mol Biol 353:1069-1080 (2005)
PubMed id: 16214170  
 
 
Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities.
D.A.Di Giusto, A.P.Sutherland, L.Jankova, S.J.Harrop, P.M.Curmi, G.C.King.
 
  ABSTRACT  
 
The serine protease inhibitor (serpin) superfamily is involved in a wide range of cellular processes including fibrinolysis, angiogenesis, apoptosis, inflammation, metastasis and viral pathogenesis. Here, we investigate the unique mousetrap inhibition mechanism of serpins through saturation mutagenesis of the P8 residue for a typical family member, plasminogen activator inhibitor-2 (PAI-2). A number of studies have proposed an important role for the P8 residue in the efficient insertion and stabilisation of the cleaved reactive centre loop (RCL), which is a key event in the serpin inhibitory mechanism. The importance of this residue for inhibition of the PAI-2 protease target urinary plasminogen activator (urokinase, uPA) is confirmed, although a high degree of tolerance to P8 substitution is observed. Out of 19 possible PAI-2 P8 mutants, 16 display inhibitory activities within an order of magnitude of the wild-type P8 Thr species. Crystal structures of complexes between PAI-2 and RCL-mimicking peptides with P8 Met or Asp mutations are determined, and structural comparison with the wild-type complex substantiates the ability of the S8 pocket to accommodate disparate side-chains. These data indicate that the identity of the P8 residue is not a determinant of efficient RCL insertion, and provide further evidence for functional plasticity of key residues within enzyme structures. Poor correlation of observed PAI-2 P8 mutant activities with a range of physicochemical, evolutionary and thermodynamic predictive indices highlights the practical limitations of existing approaches to predicting the molecular phenotype of protein variants.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. X-ray structures of PAI-2. (a) Ribbon representation of the native stressed state of PAI-2. (b) Ribbon representation of the complex between PAI-2 and a peptide mimicking the RCL. The peptide is shown in blue, where it inserts as β-strand s4A in the central A β-sheet. In each structure, the molecule is intact (uncleaved) with its RCL forming a disordered structure at the top of the molecule, indicated by the two RCL labels demarking the region of disorder.
Figure 3.
Figure 3. Structures of the P8 pocket in PAI-2:peptide complexes. (a) The structure of the wild-type P8 Thr species;^46 (b) the structure of the P8 Met mutant; and (c) the structure of the P8 Asp mutant. All views are identical, based on a least-squares superposition of the coordinates. Key hydrogen bonds are represented as dotted lines.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 353, 1069-1080) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19442270 B.J.Cochran, L.P.Gunawardhana, K.L.Vine, J.A.Lee, S.Lobov, and M.Ranson (2009).
The CD-loop of PAI-2 (SERPINB2) is redundant in the targeting, inhibition and clearance of cell surface uPA activity.
  BMC Biotechnol, 9, 43.  
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.