PDBsum entry 1ba8

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Hydrolase/hydrolase inhibitor PDB id
Protein chains
30 a.a. *
252 a.a. *
Waters ×158
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Thrombin inhibitor with a rigid tripeptidyl aldehydes
Structure: Thrombin. Chain: a. Synonym: thr-cvs1578. Thrombin. Chain: b. Synonym: thr-cvs1578. Hirugen. Chain: c. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Monomer (from PDB file)
1.80Å     R-factor:   0.152    
Authors: R.Krishnan,E.Zhang,K.Hakansson,R.K.Arni,A.Tulinsky,M.S.L.Lim O.E.Levy,J.E.Semple,T.K.Brunck
Key ref:
R.Krishnan et al. (1998). Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37, 12094-12103. PubMed id: 9724521 DOI: 10.1021/bi980840e
23-Apr-98     Release date:   27-Apr-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
30 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
252 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     catalytic activity     3 terms  


DOI no: 10.1021/bi980840e Biochemistry 37:12094-12103 (1998)
PubMed id: 9724521  
Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.
R.Krishnan, E.Zhang, K.Hakansson, R.K.Arni, A.Tulinsky, M.S.Lim-Wilby, O.E.Levy, J.E.Semple, T.K.Brunck.
The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined and refined to R values 0.152-0. 170 at 1.8-2.1 A resolution. Since the selectivity of two of the inhibitors was >1600 with respect to trypsin, the structures of trypsin-inhibited complexes of these inhibitors were also determined (R = 0.142-0.157 at 1.9-2.1 A resolution). The selectivity appears to reside in the inability of a benzenesulfonamide group to bind at the equivalent of the D-enantiomorphic S3 site of thrombin, which may be related to the lack of a 60-insertion loop in trypsin. All the inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. Differences in the binding constants of these inhibitors are correlated with their interactions with thrombin and trypsin. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism. The structures of both thrombin and trypsin complexes show similar well-defined transition states in the S1 site and at the electrophilic carbon atom and Ser195OG. The trypsin structures, however, suggest that the first step in a two-step kinetic mechanism may involve formation of a weak transition-state complex, rather than binding dominated by the P2-P4 positions.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19705489 P.Singh, A.M.LeBeau, H.Lilja, S.R.Denmeade, and J.T.Isaacs (2009).
Molecular insights into substrate specificity of prostate specific antigen through structural modeling.
  Proteins, 77, 984-993.  
18384086 I.Reulecke, G.Lange, J.Albrecht, R.Klein, and M.Rarey (2008).
Towards an integrated description of hydrogen bonding and dehydration: decreasing false positives in virtual screening with the HYDE scoring function.
  ChemMedChem, 3, 885-897.  
17372355 M.Sherawat, P.Kaur, M.Perbandt, C.Betzel, W.A.Slusarchyk, G.S.Bisacchi, C.Chang, B.L.Jacobson, H.M.Einspahr, and T.P.Singh (2007).
Structure of the complex of trypsin with a highly potent synthetic inhibitor at 0.97 A resolution.
  Acta Crystallogr D Biol Crystallogr, 63, 500-507.
PDB code: 2ayw
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
10889318 A.Scozzafava, F.Briganti, and C.T.Supuran (1999).
Protease inhibitors - Part 3. Synthesis of non-basic thrombin inhibitors incorporating pyridinium-sulfanilylguanidine moieties at the P1 site.
  Eur J Med Chem, 34, 939-952.  
10206557 J.E.Reiner, M.S.Lim-Wilby, T.K.Brunck, T.Ha-Uong, E.A.Goldman, M.A.Abelman, R.F.Nutt, J.E.Semple, and S.Y.Tamura (1999).
Investigation of the S3 site of thrombin: design, synthesis and biological activity of 4-substituted 3-amino-2-pyridones incorporating P1-argininals.
  Bioorg Med Chem Lett, 9, 895-900.  
10498222 N.K.Minami, J.E.Reiner, and J.E.Semple (1999).
Asymmetric synthesis of novel quaternary alpha-hydroxy-delta-lactam dipeptide surrogates.
  Bioorg Med Chem Lett, 9, 2625-2628.  
10498211 S.Y.Tamura, E.A.Goldman, P.W.Bergum, and J.E.Semple (1999).
Novel benzo-fused lactam scaffolds as factor Xa inhibitors.
  Bioorg Med Chem Lett, 9, 2573-2578.  
9873569 J.E.Semple (1998).
Design and construction of novel thrombin inhibitors featuring P3-P4 quaternary lactam dipeptide surrogates.
  Bioorg Med Chem Lett, 8, 2501-2506.  
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