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PDBsum entry 2d26
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protein Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
2d26

 

 

 

 

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Contents
Protein chains
336 a.a. *
30 a.a. *
223 a.a. *
Waters ×75
* Residue conservation analysis
PDB id:
2d26
Name: Hydrolase/hydrolase inhibitor
Title: Active site distortion is sufficient for proteinase inhibit second crystal structure of covalent serpin-proteinase complex
Structure: Alpha-1-antitrypsin. Chain: a. Fragment: residues 1-358. Synonym: alpha-1 protease inhibitor, alpha-1- antiproteinase. Engineered: yes. Alpha-1-antitrypsin. Chain: b. Fragment: residues 359-394. Synonym: alpha-1 protease inhibitor, alpha-1- antiproteinase.
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Expressed in: escherichia coli. Expression_system_taxid: 562. Sus scrofa. Pig. Organism_taxid: 9823.
Biol. unit: Monomer (from PQS)
Resolution:
3.30Å     R-factor:   0.251     R-free:   0.312
Authors: A.Dementiev,J.Dobo,P.G.Gettins
Key ref:
A.Dementiev et al. (2006). Active Site Distortion Is Sufficient for Proteinase Inhibition by Serpins: STRUCTURE OF THE COVALENT COMPLEX OF {alpha}1-PROTEINASE INHIBITOR WITH PORCINE PANCREATIC ELASTASE. J Biol Chem, 281, 3452-3457. PubMed id: 16321984 DOI: 10.1074/jbc.M510564200
Date:
03-Sep-05     Release date:   29-Nov-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01009  (A1AT_HUMAN) -  Alpha-1-antitrypsin from Homo sapiens
Seq:
Struc: 		418 a.a.
336 a.a.*
Protein chain
Pfam   ArchSchema ?
P01009  (A1AT_HUMAN) -  Alpha-1-antitrypsin from Homo sapiens
Seq:
Struc: 		418 a.a.
30 a.a.*
Protein chain
Pfam   ArchSchema ?
P00772  (CELA1_PIG) -  Chymotrypsin-like elastase family member 1 from Sus scrofa
Seq:
Struc: 		266 a.a.
223 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 9 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain C: E.C.3.4.21.36  - pancreatic elastase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage: Ala-|-Xaa.

 

 
DOI no: 10.1074/jbc.M510564200 J Biol Chem 281:3452-3457 (2006)
PubMed id: 16321984  
 
 
Active Site Distortion Is Sufficient for Proteinase Inhibition by Serpins: STRUCTURE OF THE COVALENT COMPLEX OF {alpha}1-PROTEINASE INHIBITOR WITH PORCINE PANCREATIC ELASTASE.
A.Dementiev, J.Dobó, P.G.Gettins.
 
  ABSTRACT  
 
We report here the x-ray structure of a covalent serpin-proteinase complex, alpha(1)-proteinase inhibitor (alpha(1)PI) with porcine pancreatic elastase (PPE), which differs from the only other x-ray structure of such a complex, that of alpha(1)PI with trypsin, in showing nearly complete definition of the proteinase. alpha(1)PI complexes with trypsin, PPE, and human neutrophil elastase (HNE) showed similar rates of deacylation and enhanced susceptibility to proteolysis by exogenous proteinases in solution. The differences between the two x-ray structures therefore cannot arise from intrinsic differences in the inhibition mechanism. However, self-proteolysis of purified complex resulted in rapid cleavage of the trypsin complex, slower cleavage of the PPE complex, and only minimal cleavage of the HNE complex. This suggests that the earlier alpha(1) PI-trypsin complex may have been proteolyzed and that the present structure is more likely to be representative of serpin-proteinase complexes. The present structure shows that active site distortion alone is sufficient for inhibition and suggests that enhanced proteolysis is not necessarily exploited in vivo.
 
  Selected figure(s)  
 
Figure 1.
Stereo ribbon representation of the structure of the a[1]PI-PPE complex. Elastase is shown in cyan. α[1]PI is shown in pink, except for the inserted RCL (red) and the remainder of β-sheet A (yellow). Ser-195 of elastase and Met-358 (P1) of α[1]PI are shown in ball-and-stick representation. 		Figure 2.
Electron density map for the catalytic residues of the complexed elastase and the α[1]PI P1 methionine (stereo). Continuous density links the backbone of the methionine 358 to the γO of Ser-195, indicating the presence of a covalent ester linkage between the serpin and the proteinase.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 3452-3457) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20459833 D.H.Bryant, M.Moll, B.Y.Chen, V.Y.Fofanov, and L.E.Kavraki (2010).
Analysis of substructural variation in families of enzymatic proteins with applications to protein function prediction.
  BMC Bioinformatics, 11, 242.  
21062218 L.Muszbek, Z.Bereczky, B.Kovács, and I.Komáromi (2010).
Antithrombin deficiency and its laboratory diagnosis.
  Clin Chem Lab Med, 48, S67-S78.  
19245336 B.Gooptu, and D.A.Lomas (2009).
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
  Annu Rev Biochem, 78, 147-176.  
19661062 B.Richard, R.Swanson, and S.T.Olson (2009).
The signature 3-O-sulfo group of the anticoagulant heparin sequence is critical for heparin binding to antithrombin but is not required for allosteric activation.
  J Biol Chem, 284, 27054-27064.  
19492109 C.Boudier, A.S.Klymchenko, Y.Mely, and A.Follenius-Wund (2009).
Local environment perturbations in alpha(1)-antitrypsin monitored by a ratiometric fluorescent label.
  Photochem Photobiol Sci, 8, 814-821.  
19010776 G.Izaguirre, A.R.Rezaie, and S.T.Olson (2009).
Engineering functional antithrombin exosites in alpha1-proteinase inhibitor that specifically promote the inhibition of factor Xa and factor IXa.
  J Biol Chem, 284, 1550-1558.  
19439404 J.K.Jensen, K.Dolmer, and P.G.Gettins (2009).
Specificity of binding of the low density lipoprotein receptor-related protein to different conformational states of the clade E serpins plasminogen activator inhibitor-1 and proteinase nexin-1.
  J Biol Chem, 284, 17989-17997.  
18686007 M.Nadai, J.Bally, M.Vitel, C.Job, G.Tissot, J.Botterman, and M.Dubald (2009).
High-level expression of active human alpha1-antitrypsin in transgenic tobacco chloroplasts.
  Transgenic Res, 18, 173-183.  
19401470 P.G.Gettins, and S.T.Olson (2009).
Exosite determinants of serpin specificity.
  J Biol Chem, 284, 20441-20445.  
17805946 B.Jelinek, G.Katona, K.Fodor, I.Venekei, and L.Gráf (2008).
The crystal structure of a trypsin-like mutant chymotrypsin: the role of position 226 in the activity and specificity of S189D chymotrypsin.
  Protein J, 27, 79-87.
PDB code: 2jet
18375953 B.Richard, R.Swanson, S.Schedin-Weiss, B.Ramirez, G.Izaguirre, P.G.Gettins, and S.T.Olson (2008).
Characterization of the conformational alterations, reduced anticoagulant activity, and enhanced antiangiogenic activity of prelatent antithrombin.
  J Biol Chem, 283, 14417-14429.  
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.  
18768472 X.Huang, R.Swanson, G.J.Broze, and S.T.Olson (2008).
Kinetic characterization of the protein Z-dependent protease inhibitor reaction with blood coagulation factor Xa.
  J Biol Chem, 283, 29770-29783.  
18184582 X.Zheng, P.L.Wintrode, and M.R.Chance (2008).
Complementary structural mass spectrometry techniques reveal local dynamics in functionally important regions of a metastable serpin.
  Structure, 16, 38-51.  
  19164889 D.Belorgey, P.Hägglöf, S.Karlsson-Li, and D.A.Lomas (2007).
Protein misfolding and the serpinopathies.
  Prion, 1, 15-20.  
17962402 L.Liu, N.Mushero, L.Hedstrom, and A.Gershenson (2007).
Short-lived protease serpin complexes: partial disruption of the rat trypsin active site.
  Protein Sci, 16, 2403-2411.  
16543139 H.R.Stennicke, and G.S.Salvesen (2006).
Chemical ligation--an unusual paradigm in protease inhibition.
  Mol Cell, 21, 727-728.  
16820297 J.A.Huntington (2006).
Shape-shifting serpins--advantages of a mobile mechanism.
  Trends Biochem Sci, 31, 427-435.  
17042782 S.Skeldal, J.V.Larsen, K.E.Pedersen, H.H.Petersen, R.Egelund, A.Christensen, J.K.Jensen, J.Gliemann, and P.A.Andreasen (2006).
Binding areas of urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex for endocytosis receptors of the low-density lipoprotein receptor family, determined by site-directed mutagenesis.
  FEBS J, 273, 5143-5159.  
16796670 W.H.Schwarz, and V.V.Zverlov (2006).
Protease inhibitors in bacteria: an emerging concept for the regulation of bacterial protein complexes?
  Mol Microbiol, 60, 1323-1326.  
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.

 

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