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PDBsum entry 1tbz

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1tbz
Jmol
Contents
Protein chains
25 a.a. *
251 a.a. *
Ligands
ASP-PHE-GLU-GLU-
ILE-PRO-GLU-GLU-
TYS-LEU
00Q
Metals
_NA ×2
Waters ×123
* Residue conservation analysis
PDB id:
1tbz
Name: Hydrolase/hydrolase inhibitor
Title: Human thrombin with active site n-methyl-d phenylalanyl-n-[5 (aminoiminomethyl)amino]-1-{{benzothiazolyl)carbonyl] butyl prolinamide trifluroacetate and exosite-hirugen
Structure: Alpha-thrombin. Chain: l. Alpha-thrombin. Chain: h. Hirugen. Chain: i
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: plasma. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Tetramer (from PQS)
Resolution:
2.30Å     R-factor:   0.158    
Authors: J.H.Matthews,R.Krishnan,M.J.Costanzo,B.E.Maryanoff,A.Tulinsk
Key ref: J.H.Matthews et al. (1996). Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site. Biophys J, 71, 2830-2839. PubMed id: 8913620
Date:
05-Feb-98     Release date:   27-May-98    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
25 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
251 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.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     blood coagulation   2 terms 
  Biochemical function     catalytic activity     3 terms  

 

 
Biophys J 71:2830-2839 (1996)
PubMed id: 8913620  
 
 
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.
J.H.Matthews, R.Krishnan, M.J.Costanzo, B.E.Maryanoff, A.Tulinsky.
 
  ABSTRACT  
 
Structures of the blood clotting enzyme thrombin complexed with hirugen and two active site inhibitors, RWJ-50353 10080(N-methyl-D-phenylalanyl-N-[5-[(aminoiminomethyl)amino]-1- [[(2-benzothiazolyl)carbonyl]butyl]-L-prolinamide trifluoroacetate hydrate) and RWJ-50215 (N-[4-(aminoiminomethyl)amino-1-[2- (thiazol-2-ylcarbonylethyl)piperidin- 1-ylcarbonyl]butyl]-5-(dimethylamino)naphthalenesulfonamide trifluoroacetate hydrate), were determined by x-ray crystallography. The refinements converged at R values of 0.158 in the 7.0-2.3-A range for RWJ-50353 and 0.155 in the 7.0-1.8-A range for RWJ-50215. Interactions between the protein and the thiazole rings of the two inhibitors provide new valuable information about the S1' binding site of thrombin. The RWJ-50353 inhibitor consists of an S1'-binding benzothiazole group linked to the D-Phe-Pro-Arg chloromethyl ketone motif. Interactions with the S1-S3 sites are similar to the D-phenylalanyl-prolyl-arginyl chloromethylketone structure. In RWJ-50215, a S1'-binding 2-ketothiazole group was added to the thrombin inhibitor-like framework of dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. The geometry at the S1-S3 sites here is also similar to that of the parent compound. The benzothiazole and 2-ketothiazole groups bind in a cavity surrounded by His57, Tyr60A, Trp60D, and Lys60F. This location of the S1' binding site is consistent with previous structures of thrombin complexes with hirulog-3, CVS-995, and hirutonin-2 and -6. The ring nitrogen of the RWJ-50353 benzothiazole forms a hydrogen bond with His57, and Lys60F reorients because of close contacts. The oxygen and nitrogen of the ketothiazole of RWJ-50215 hydrogen bond with the NZ atom of Lys60F.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19235177 M.I.Zavodszky, A.Rohatgi, J.R.Van Voorst, H.Yan, and L.A.Kuhn (2009).
Scoring ligand similarity in structure-based virtual screening.
  J Mol Recognit, 22, 280-292.  
10694407 J.J.Slon-Usakiewicz, J.Sivaraman, Y.Li, M.Cygler, and Y.Konishi (2000).
Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures.
  Biochemistry, 39, 2384-2391.
PDB codes: 1eoj 1eol
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
11053836 R.Recacha, M.J.Costanzo, B.E.Maryanoff, M.Carson, L.DeLucas, and D.Chattopadhyay (2000).
Structure of human alpha-thrombin complexed with RWJ-51438 at 1.7 A: unusual perturbation of the 60A-60I insertion loop.
  Acta Crystallogr D Biol Crystallogr, 56, 1395-1400.
PDB code: 1doj
10545181 A.Betz, P.W.Wong, and U.Sinha (1999).
Inhibition of factor Xa by a peptidyl-alpha-ketothiazole involves two steps. Evidence for a stabilizing conformational change.
  Biochemistry, 38, 14582-14591.  
10531473 R.Recacha, M.Carson, M.J.Costanzo, B.Maryanoff, L.J.DeLucas, and D.Chattopadhyay (1999).
Structure of the RWJ-51084-bovine pancreatic beta-trypsin complex at 1.8 A.
  Acta Crystallogr D Biol Crystallogr, 55, 1785-1791.
PDB code: 1qcp
9618463 K.Kamata, H.Kawamoto, T.Honma, T.Iwama, and S.H.Kim (1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
  Proc Natl Acad Sci U S A, 95, 6630-6635.
PDB codes: 1xka 1xkb
9724521 R.Krishnan, E.Zhang, K.Hakansson, R.K.Arni, A.Tulinsky, M.S.Lim-Wilby, O.E.Levy, J.E.Semple, and T.K.Brunck (1998).
Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.
  Biochemistry, 37, 12094-12103.
PDB codes: 1ba8 1bb0 1ca8 1yyy 1zzz
  9792427 S.Tada, and J.J.Blow (1998).
The replication licensing system.
  Biol Chem, 379, 941-949.  
9667850 W.C.Ripka (1997).
New thrombin inhibitors in cardiovascular disease.
  Curr Opin Chem Biol, 1, 242-253.  
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.