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PDBsum entry 1an1

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protein metals Protein-protein interface(s) links
Complex (serine protease/inhibitor) PDB id
1an1
Jmol
Contents
Protein chains
223 a.a. *
40 a.a. *
Metals
_CA
Waters ×138
* Residue conservation analysis
PDB id:
1an1
Name: Complex (serine protease/inhibitor)
Title: Leech-derived tryptase inhibitor/trypsin complex
Structure: Trypsin. Chain: e. Synonym: ldti. Engineered: yes. Tryptase inhibitor. Chain: i. Engineered: yes. Mutation: yes
Source: Sus scrofa. Pig. Organism_taxid: 9823. Organ: pancreas. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421. Organ: salivary glands. Expressed in: saccharomyces cerevisiae.
Biol. unit: Dimer (from PQS)
Resolution:
2.03Å     R-factor:   0.170     R-free:   0.228
Authors: J.P.Priestle,S.Di Marco
Key ref:
S.Di Marco and J.P.Priestle (1997). Structure of the complex of leech-derived tryptase inhibitor (LDTI) with trypsin and modeling of the LDTI-tryptase system. Structure, 5, 1465-1474. PubMed id: 9384562 DOI: 10.1016/S0969-2126(97)00296-7
Date:
26-Jun-97     Release date:   01-Jul-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00761  (TRYP_PIG) -  Trypsin
Seq:
Struc:
231 a.a.
223 a.a.*
Protein chain
Pfam   ArchSchema ?
P80424  (LDTI_HIRME) -  Leech-derived tryptase inhibitor C
Seq:
Struc:
46 a.a.
40 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain E: E.C.3.4.21.4  - Trypsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     digestion   4 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
DOI no: 10.1016/S0969-2126(97)00296-7 Structure 5:1465-1474 (1997)
PubMed id: 9384562  
 
 
Structure of the complex of leech-derived tryptase inhibitor (LDTI) with trypsin and modeling of the LDTI-tryptase system.
S.Di Marco, J.P.Priestle.
 
  ABSTRACT  
 
BACKGROUND: Tryptase is a trypsin-like serine proteinase stored in the cytoplasmic granules of mast cells, which has been implicated in a number of mast cell related disorders such as asthma and rheumatoid arthritis. Unlike almost all other serine proteinases, tryptase is fully active in plasma and in the extracellular space, as there are no known natural inhibitors of tryptase in humans. Leech-derived tryptase inhibitor (LDTI), a protein of 46 amino acids, is the first molecule found to bind tightly to and specifically inhibit human tryptase in the nanomolar range. LDTI also inhibits trypsin and chymotrypsin with similar affinities. The structure of LDTI in complex with an inhibited proteinase could be used as a template for the development of low molecular weight tryptase inhibitors. RESULTS: The crystal structure of the complex between trypsin and LDTI was solved at 2.0 A resolution and a model of the LDTI-tryptase complex was created, based on this X-ray structure. LDTI has a very similar fold to the third domain of the turkey ovomucoid inhibitor. LDTI interacts with trypsin almost exclusively through its binding loop (residues 3-10) and especially through the sidechain of the specificity residue Lys8. Our modeling studies indicate that these interactions are maintained in the LDTI-tryptase complex. CONCLUSIONS: The insertion of nine residues after residue 174 in tryptase, relative to trypsin and chymotrypsin, prevents inhibition by other trypsin inhibitors and is certainly responsible for the higher specificity of tryptase relative to trypsin. In LDTI, the disulfide bond between residues 4 and 25 causes a sharp turn from the binding loop towards the N terminus, holding the N terminus away from the 174 loop of tryptase.
 
  Selected figure(s)  
 
Figure 6.
Figure 6. Electrostatic potential surface representation of the model of tryptase. (a) The region around the active site, including the binding loop of LDTI. (b) The same view as (a) but rotated 180°. The sidechains of the specificity residues P4 to P3' of LDTI are labeled (nomenclature of Berger and Schechter [26]), although Ala5 (P4) is hidden under the tryptase 174 insertion loop and Lys8 (P1) is buried in the S1 specificity pocket. The highly electronegative active-site area (red) corresponds well to the positively charged LDTI molecule (pI > 10). The concentrated positively charged region (blue) in tryptase, shown at the bottom of (b), could be responsible for heparin binding. (The figure was made with the program GRASP [43].)
 
  The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 1465-1474) copyright 1997.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20812859 J.L.Arolas, and S.Ventura (2011).
Protease inhibitors as models for the study of oxidative folding.
  Antioxid Redox Signal, 14, 97.  
19820233 D.Pantoja-Uceda, J.L.Arolas, F.X.Aviles, J.Santoro, S.Ventura, and C.P.Sommerhoff (2009).
Deciphering the structural basis that guides the oxidative folding of leech-derived tryptase inhibitor.
  J Biol Chem, 284, 35612-35620.
PDB codes: 2kmo 2kmp 2kmq 2kmr
18004973 J.L.Arolas, S.Bronsoms, F.X.Aviles, S.Ventura, and C.P.Sommerhoff (2008).
Oxidative folding of leech-derived tryptase inhibitor via native disulfide-bonded intermediates.
  Antioxid Redox Signal, 10, 77-86.  
18058774 O.Avrutina, H.U.Schmoldt, D.Gabrijelcic-Geiger, A.Wentzel, H.Frauendorf, C.P.Sommerhoff, U.Diederichsen, and H.Kolmar (2008).
Head-to-tail cyclized cystine-knot peptides by a combined recombinant and chemical route of synthesis.
  Chembiochem, 9, 33-37.  
12577262 J.B.Mitchell, and J.Smith (2003).
D-amino acid residues in peptides and proteins.
  Proteins, 50, 563-571.  
  11906611 D.Scarpi, J.D.McBride, and R.J.Leatherbarrow (2002).
Inhibition of human beta-tryptase by Bowman-Birk inhibitor derived peptides.
  J Pept Res, 59, 90-93.  
11154069 F.Erba, L.Fiorucci, C.P.Sommerhoff, M.Coletta, and F.Ascoli (2000).
Kinetic and thermodynamic analysis of leech-derived tryptase inhibitor interaction with bovine tryptase and bovine trypsin.
  Biol Chem, 381, 1117-1122.  
10771427 U.Rester, M.Moser, R.Huber, and W.Bode (2000).
L-Isoaspartate 115 of porcine beta-trypsin promotes crystallization of its complex with bdellastasin.
  Acta Crystallogr D Biol Crystallogr, 56, 581-588.
PDB code: 1eja
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