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PDBsum entry 1ta6
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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1ta6

 

 

 

 

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Contents
Protein chains
276 a.a. *
11 a.a. *
Ligands
177
Waters ×143
* Residue conservation analysis
PDB id:
1ta6
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of thrombin in complex with compound 14b
Structure: Thrombin. Chain: a. Fragment: alpha-thrombin. Synonym: coagulation factor ii. Hirudin. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: pancreas. Synthetic: yes
Biol. unit: Dimer (from PQS)
Resolution:
1.90Å     R-factor:   0.186    
Authors: T.J.Tucker,S.F.Brady,W.C.Lumma,S.D.Lewis,S.J.Gardel,A.M.Naylor-Olsen, Y.Yan,J.T.Sisko,K.J.Stauffer,B.Y.Lucas,J.J.Lynch,J.J.Cook, M.T.Stranieri,M.A.Holahan,E.A.Lyle,E.P.Baskin,I.-W.Chen, K.B.Dancheck,J.A.Krueger,C.M.Cooper,J.P.Vacca
Key ref: T.J.Tucker et al. (1998). Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. J Med Chem, 41, 3210-3219. PubMed id: 9703466 DOI: 10.1021/jm9801713
Date:
19-May-04     Release date:   08-Jun-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
276 a.a.
Protein chain
Pfam   ArchSchema ?
P28504  (HIR2_HIRME) -  Hirudin-2 from Hirudo medicinalis
Seq:
Struc: 		65 a.a.
11 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: 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.

 

 
DOI no: 10.1021/jm9801713 J Med Chem 41:3210-3219 (1998)
PubMed id: 9703466  
 
 
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.
T.J.Tucker, S.F.Brady, W.C.Lumma, S.D.Lewis, S.J.Gardell, A.M.Naylor-Olsen, Y.Yan, J.T.Sisko, K.J.Stauffer, B.J.Lucas, J.J.Lynch, J.J.Cook, M.T.Stranieri, M.A.Holahan, E.A.Lyle, E.P.Baskin, I.W.Chen, K.B.Dancheck, J.A.Krueger, C.M.Cooper, J.P.Vacca.
 
  ABSTRACT  
 
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20953472 H.G.Wallnoefer, T.Fox, K.R.Liedl, and C.S.Tautermann (2010).
Dispersion dominated halogen-π interactions: energies and locations of minima.
  Phys Chem Chem Phys, 12, 14941-14949.  
18196461 J.W.Liebeschuetz (2008).
Evaluating docking programs: keeping the playing field level.
  J Comput Aided Mol Des, 22, 229-238.  
18434503 Y.N.Imai, Y.Inoue, I.Nakanishi, and K.Kitaura (2008).
Cl-pi interactions in protein-ligand complexes.
  Protein Sci, 17, 1129-1137.  
17384076 E.L.Wu, Y.Mei, K.Han, and J.Z.Zhang (2007).
Quantum and molecular dynamics study for binding of macrocyclic inhibitors to human alpha-thrombin.
  Biophys J, 92, 4244-4253.  
16511824 R.Fasan, R.L.Dias, K.Moehle, O.Zerbe, D.Obrecht, P.R.Mittl, M.G.Grütter, and J.A.Robinson (2006).
Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
  Chembiochem, 7, 515-526.
PDB code: 2axi
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.  
11206465 U.Heinelt, S.Herok, H.Matter, and P.Wildgoose (2001).
Solid-phase optimisation of achiral amidinobenzyl indoles as potent and selective factor Xa inhibitors.
  Bioorg Med Chem Lett, 11, 227-230.  
10328293 J.Ambler, D.Bentley, L.Brown, K.Dunnet, D.Farr, D.Janus, D.Le Grand, K.Menear, M.Mercer, M.Talbot, M.Tweed, and B.Wathey (1999).
The discovery of orally available thrombin inhibitors: optimisation of the P1 pharmacophore.
  Bioorg Med Chem Lett, 9, 1103-1108.  
10189177 P.E.Sanderson (1999).
Small, noncovalent serine protease inhibitors.
  Med Res Rev, 19, 179-197.  
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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