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PDBsum entry 1ths
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protein Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1ths

 

 

 

 

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Contents
Protein chains
33 a.a. *
252 a.a. *
11 a.a. *
Waters ×140
* Residue conservation analysis
PDB id:
1ths
Name: Hydrolase/hydrolase inhibitor
Title: Structures of thrombin complexes with a designed and a natural exosite inhibitor
Structure: Alpha-thrombin (small subunit). Chain: l. Engineered: yes. Alpha-thrombin (large subunit). Chain: h. Engineered: yes. Synthetic inhibitor. Chain: i. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Tissue: blood. Synthetic: yes
Biol. unit: Trimer (from PQS)
Resolution:
2.20Å     R-factor:   0.161    
Authors: X.Qiu,M.Yin,K.P.Padmanabhan,J.L.Krstenansky,A.Tulinsky
Key ref: X.Qiu et al. (1993). Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor. J Biol Chem, 268, 20318-20326. PubMed id: 8376390
Date:
16-Jun-93     Release date:   31-Jan-94    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
33 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
252 a.a.
Protein chain
No UniProt id for this chain
Struc: 11 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains L, H: E.C.3.4.21.5  - thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

 

 
J Biol Chem 268:20318-20326 (1993)
PubMed id: 8376390  
 
 
Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor.
X.Qiu, M.Yin, K.P.Padmanabhan, J.L.Krstenansky, A.Tulinsky.
 
  ABSTRACT  
 
The structures of two hirudin-based fibrinogen recognition exosite peptide inhibitors with significantly different sequences complexed with alpha-thrombin at a site distinct from the active site (exosite) have been determined crystallographically at 2.2 and 2.3 A resolution. One is a designed synthetic peptide with some nonconventional amino acid residues (MDL-28050), and the other is a natural COOH-terminal peptide isolated from the leech Hirudinaria manillensis (hirullin P18). The structures have been refined by restrained least squares methods to R values of 0.161 and 0.155, respectively. The first stretch of each peptide, corresponding to hirudin 55-59, associates with thrombin similar to hirudin and hirugen (hirudin 53-64). Although the remaining residues of the inhibitors interact with and bind to thrombin, the binding is accomplished. through a rigid body conformational adjustment of the peptide with respect to the conformation displayed by hirudin and hirugen (40 degrees rotation about the Ile59, CA-C bond). This causes the side groups of cyclohexylalanine 64' of MDL-28050 and Ile60, of hirullin to point in the opposite direction of the all important Tyr63, ring of hirudin and hirugen but permits the residues to penetrate and interact with the 3(10) turn hydrophobic binding pocket of thrombin. Thus, the hydrophobic interaction is accomplished in a different way by virtue of the substrate conformational readjustment. The results show that the first stretch of peptide makes concerted and efficient binding interactions with thrombin, and the peptide positions of the inhibitors are fairly specific and homologous so that the stretch appears to be related to specific recognition associated with the exosite. The relative flexibility of structure and sequence of the second stretch is a display of tolerance of imprecision by thrombin in its COOH-terminal hydrophobic association with hirudin-based inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
14607082 J.A.Huntington, and T.P.Baglin (2003).
Targeting thrombin--rational drug design from natural mechanisms.
  Trends Pharmacol Sci, 24, 589-595.  
10380350 A.Lombardi, G.De Simone, S.Galdiero, N.Staiano, F.Nastri, and V.Pavone (1999).
From natural to synthetic multisite thrombin inhibitors.
  Biopolymers, 51, 19-39.  
10504391 T.Steinmetzer, M.Renatus, S.Künzel, A.Eichinger, W.Bode, P.Wikström, J.Hauptmann, and J.Stürzebecher (1999).
Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines.
  Eur J Biochem, 265, 598-605.
PDB code: 1qur
9894338 F.Shi, P.J.Hogg, D.J.Winzor, and C.M.Jackson (1998).
Evidence for multiple enzyme site involvement in the modulation of thrombin activity by products of prothrombin proteolysis.
  Biophys Chem, 75, 187-199.  
  9521099 G.De Simone, A.Lombardi, S.Galdiero, F.Nastri, R.Della Morte, N.Staiano, C.Pedone, M.Bolognesi, and V.Pavone (1998).
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.
  Protein Sci, 7, 243-253.
PDB code: 5gds
  9792427 S.Tada, and J.J.Blow (1998).
The replication licensing system.
  Biol Chem, 379, 941-949.  
8679942 F.Ni, K.A.Carpenter, D.R.Ripoll, S.D.Sanderson, and T.E.Hugli (1996).
Stabilization of an isolated helical capping box in solution by hydrophobic interactions: evidence from the NMR study of bioactive peptides from the C-terminus of human C5a anaphylatoxin.
  Biopolymers, 38, 31-41.  
  8868478 R.Krishnan, A.Tulinsky, G.P.Vlasuk, D.Pearson, P.Vallar, P.Bergum, T.K.Brunck, and W.C.Ripka (1996).
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic.
  Protein Sci, 5, 422-433.
PDB code: 1dit
8569452 P.Ascenzi, G.Amiconi, W.Bode, M.Bolognesi, M.Coletta, and E.Menegatti (1995).
Proteinase inhibitors from the European medicinal leech Hirudo medicinalis: structural, functional and biomedical aspects.
  Mol Aspects Med, 16, 215-313.  
  7756983 J.Vijayalakshmi, K.P.Padmanabhan, K.G.Mann, and A.Tulinsky (1994).
The isomorphous structures of prethrombin2, hirugen-, and PPACK-thrombin: changes accompanying activation and exosite binding to thrombin.
  Protein Sci, 3, 2254-2271.
PDB codes: 1hag 1hah 1hai
7712286 M.T.Stubbs, and W.Bode (1994).
Coagulation factors and their inhibitors.
  Curr Opin Struct Biol, 4, 823-832.  
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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