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PDBsum entry 1hdt
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Hydrolase/hydrolase inhibitor PDB id
1hdt

 

 

 

 

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Contents
Protein chains
33 a.a. *
259 a.a. *
11 a.a. *
Ligands
0E7
Waters ×95
* Residue conservation analysis
PDB id:
1hdt
Name: Hydrolase/hydrolase inhibitor
Title: Structure of a retro-binding peptide inhibitor complexed with human alpha-thrombin
Structure: Alpha-thrombin. Chain: l. Alpha-thrombin. Chain: h. Hirugen peptide. Chain: p. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Tetramer (from PQS)
Resolution:
2.60Å     R-factor:   0.204    
Authors: L.Tabernero,J.Sack
Key ref: L.Tabernero et al. (1995). Structure of a retro-binding peptide inhibitor complexed with human alpha-thrombin. J Mol Biol, 246, 14-20. PubMed id: 7853394
Date:
25-Jul-94     Release date:   15-Oct-95    
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.
259 a.a.
Protein chain
Pfam   ArchSchema ?
P28509  (HIR3_HIRME) -  Hirudin-3 from Hirudo medicinalis
Seq:
Struc: 		65 a.a.
11 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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 Mol Biol 246:14-20 (1995)
PubMed id: 7853394  
 
 
Structure of a retro-binding peptide inhibitor complexed with human alpha-thrombin.
L.Tabernero, C.Y.Chang, S.L.Ohringer, W.F.Lau, E.J.Iwanowicz, W.C.Han, T.C.Wang, S.M.Seiler, D.G.Roberts, J.S.Sack.
 
  ABSTRACT  
 
The crystallographic structure of the ternary complex between human alpha-thrombin, hirugen and the peptidyl inhibitor Phe-alloThr-Phe-O-CH3, which is acylated at its N terminus with 4-guanidino butanoic acid (BMS-183507), has been determined at 2.6 A resolution. The structure reveals a unique "retro-binding" mode for this tripeptide active site inhibitor. The inhibitor binds with its alkyl-guanidine moiety in the primary specificity pocket and its two phenyl rings occupying the hydrophobic proximal and distal pockets of the thrombin active site. In this arrangement the backbone of the tripeptide forms a parallel beta-strand to the thrombin main-chain at the binding site. This is opposite to the orientation of the natural substrate, fibrinogen, and all the small active site-directed thrombin inhibitors whose bound structures have been previously reported. BMS-183507 is the first synthetic inhibitor proved to bind in a retro-binding fashion to thrombin, in a fashion similar to that of the N-terminal residues of the natural inhibitor hirudin. Furthermore, this new potent thrombin inhibitor (Ki = 17.2 nM) is selective for thrombin over other serine proteases tested and may be a template to be considered in designing hirudin-based thrombin inhibitors with interactions at the specificity pocket.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
15635223 E.Toyota, H.Sekizaki, Y.U.Takahashi, K.Itoh, and K.Tanizawa (2005).
Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor.
  Chem Pharm Bull (Tokyo), 53, 22-26.  
15389730 S.Srivastava, L.N.Goswami, and D.K.Dikshit (2005).
Progress in the design of low molecular weight thrombin inhibitors.
  Med Res Rev, 25, 66-92.  
10713516 R.Krishnan, I.Mochalkin, R.Arni, and A.Tulinsky (2000).
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1.
  Acta Crystallogr D Biol Crystallogr, 56, 294-303.
PDB codes: 1c4u 1c4v 1c4y 1d6w 1d9i
10739913 R.Krishnan, J.E.Sadler, and A.Tulinsky (2000).
Structure of the Ser195Ala mutant of human alpha--thrombin complexed with fibrinopeptide A(7--16): evidence for residual catalytic activity.
  Acta Crystallogr D Biol Crystallogr, 56, 406-410.
PDB code: 1dm4
  10716178 R.St Charles, K.Padmanabhan, R.V.Arni, K.P.Padmanabhan, and A.Tulinsky (2000).
Structure of tick anticoagulant peptide at 1.6 A resolution complexed with bovine pancreatic trypsin inhibitor.
  Protein Sci, 9, 265-272.
PDB code: 1d0d
  10210187 A.Lombardi, G.De Simone, F.Nastri, S.Galdiero, R.Della Morte, N.Staiano, C.Pedone, M.Bolognesi, and V.Pavone (1999).
The crystal structure of alpha-thrombin-hirunorm IV complex reveals a novel specificity site recognition mode.
  Protein Sci, 8, 91-95.
PDB code: 4thn
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.  
10089309 I.Mochalkin, and A.Tulinsky (1999).
Structures of thrombin retro-inhibited with SEL2711 and SEL2770 as they relate to factor Xa binding.
  Acta Crystallogr D Biol Crystallogr, 55, 785-793.
PDB codes: 7kme 8kme
10089499 C.L.Strickland, J.M.Fevig, R.A.Galemmo, B.L.Wells, C.A.Kettner, and P.C.Weber (1998).
Biochemical and crystallographic characterization of homologous non-peptidic thrombin inhibitors having alternate binding modes.
  Acta Crystallogr D Biol Crystallogr, 54, 1207-1215.  
  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.  
  9232642 N.Y.Chirgadze, D.J.Sall, V.J.Klimkowski, D.K.Clawson, S.L.Briggs, R.Hermann, G.F.Smith, D.S.Gifford-Moore, and J.P.Wery (1997).
The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.
  Protein Sci, 6, 1412-1417.
PDB code: 1d4p
8951649 A.Caflisch (1996).
Computational combinatorial ligand design: application to human alpha-thrombin.
  J Comput Aided Mol Des, 10, 372-396.  
8913620 J.H.Matthews, R.Krishnan, M.J.Costanzo, B.E.Maryanoff, and A.Tulinsky (1996).
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.
  Biophys J, 71, 2830-2839.
PDB codes: 1a4w 1tbz
  8745399 M.F.Malley, L.Tabernero, C.Y.Chang, S.L.Ohringer, D.G.Roberts, J.Das, and J.S.Sack (1996).
Crystallographic determination of the structures of human alpha-thrombin complexed with BMS-186282 and BMS-189090.
  Protein Sci, 5, 221-228.
PDB codes: 1bmm 1bmn
8786410 P.D.Grootenhuis, and M.Karplus (1996).
Functionality map analysis of the active site cleft of human thrombin.
  J Comput Aided Mol Des, 10, 1.  
7582978 W.F.Lau, L.Tabernero, J.S.Sack, and E.J.Iwanowicz (1995).
Molecular modeling studies of novel retro-binding tripeptide active-site inhibitors of thrombin.
  Bioorg Med Chem, 3, 1039-1048.  
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 codes are shown on the right.

 

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