PDBsum entry 1a4w

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
Jmol PyMol
Protein chains
26 a.a. *
248 a.a. *
_NA ×2
Waters ×157
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structures of thrombin with thiazole-containing inhi probes of the s1' binding site
Structure: Alpha-thrombin (small subunit). Chain: l. Alpha-thrombin (large subunit). Chain: h. Hirugen. Chain: i. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Tissue: blood.
Biol. unit: Tetramer (from PQS)
1.80Å     R-factor:   0.155    
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
06-Feb-98     Release date:   29-Apr-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
26 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
248 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     blood coagulation   2 terms 
  Biochemical function     calcium ion binding     2 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.
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.  
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