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PDBsum entry 1d4p
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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1d4p

 

 

 

 

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Contents
Protein chains
28 a.a. *
250 a.a. *
12 a.a. *
Ligands
NAG
BPP
Metals
_NA ×2
Waters ×116
* Residue conservation analysis
PDB id:
1d4p
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of human alpha thrombin in complex with 5- amidinoindole-4-benzylpiperidine inhibitor
Structure: Alpha-thrombin. Chain: a. Fragment: light chain. Engineered: yes. Alpha-thrombin. Chain: b. Fragment: heavy chain. Engineered: yes. Hirugen.
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Trimer (from PQS)
Resolution:
2.07Å     R-factor:   0.184     R-free:   0.231
Authors: N.Y.Chirgadze
Key ref:
N.Y.Chirgadze et al. (1997). The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor. Protein Sci, 6, 1412-1417. PubMed id: 9232642 DOI: 10.1002/pro.5560060705
Date:
04-Oct-99     Release date:   20-Oct-99    
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.
28 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
250 a.a.
Protein chain
Pfam   ArchSchema ?
P01050  (HIRV1_HIRME) -  Hirudin variant-1 from Hirudo medicinalis
Seq:
Struc: 		65 a.a.
12 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 A, B: 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: 10.1002/pro.5560060705 Protein Sci 6:1412-1417 (1997)
PubMed id: 9232642  
 
 
The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.
N.Y.Chirgadze, D.J.Sall, V.J.Klimkowski, D.K.Clawson, S.L.Briggs, R.Hermann, G.F.Smith, D.S.Gifford-Moore, J.P.Wery.
 
  ABSTRACT  
 
The crystal structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A resolution by the method of X-ray crystallography. The final model of the complex has a crystallographic R-value of 21.5% (Rfree = 23.1%) with 0.014 A and 2.4 degrees standard deviation from ideal bond lengths and angles, respectively. Well-defined electron density was observed for the inhibitor in the active site. The inhibitor binds to the active site in an L-shaped manner, mimicking the bound conformation of the tripeptide arginal series of thrombin inhibitors (Chirgadze NY et al., 1992, American Crystallographic Association Meeting 20: 116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridge with Asp 189 within the specificity pocket, while the 4-benzylpiperidine side chain engages in a number of hydrophobic interactions at the S2 and S3 binding sites. The inhibitor does not interact in any fashion with the active site sequence Ser 214-Gly 216, as occurs with many of the inhibitors studied previously. The indole N-H of the inhibitor forms a hydrogen bond to the gamma-oxygen of the catalytic serine (Ser 195).
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Stereo iew of 5-amidinoindole4-benzylpiperidine bond to the active site of human a-thrombin. heomittedelectrondensity mapcorresponding to theinhibitor,whichwasued to position LY178550 intheactive site, is shown. The mapiscontouredat 1.0 level,with (2F, - a;) oefficientsat a resoluion of 2.07 A. 		Figure 4.
Fig. 4. Superposition of heX-ray crystal structures of thenonpeptidalLY178550(thickline)and tripeptide rginaLY288570 (thin line), each ompleed with human a-thrombin. The ovelay demonstrates hat each binds in a similar manner,butwith interaction points (see text). An -ray structure of theLY288570complexhasbeendeterminedpreviously in laboratoryat2.2 A resolution.
 
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1997, 6, 1412-1417) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18852137 J.R.Chevillet, G.J.Park, A.Bedalov, J.A.Simon, and V.I.Vasioukhin (2008).
Identification and characterization of small-molecule inhibitors of hepsin.
  Mol Cancer Ther, 7, 3343-3351.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
  11186232 B.A.Citron, I.V.Smirnova, P.M.Arnold, and B.W.Festoff (2000).
Upregulation of neurotoxic serine proteases, prothrombin, and protease-activated receptor 1 early after spinal cord injury.
  J Neurotrauma, 17, 1191-1203.  
  10739244 N.Y.Chirgadze, D.J.Sall, S.L.Briggs, D.K.Clawson, M.Zhang, G.F.Smith, and R.W.Schevitz (2000).
The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors.
  Protein Sci, 9, 29-36.
PDB codes: 1d3d 1d3p 1d3q 1d3t
10230612 C.Dominguez, D.E.Duffy, Q.Han, R.S.Alexander, R.A.Galemmo, J.M.Park, P.C.Wong, E.C.Amparo, R.M.Knabb, J.Luettgen, and R.R.Wexler (1999).
Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors.
  Bioorg Med Chem Lett, 9, 925-930.  
10387040 H.Jhoti, A.Cleasby, S.Reid, P.J.Thomas, M.Weir, and A.Wonacott (1999).
Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.
  Biochemistry, 38, 7969-7977.
PDB codes: 1qhr 1qj1 1qj6 1qj7
10509932 M.R.Wiley, L.C.Weir, S.L.Briggs, N.Y.Chirgadze, D.Clawson, D.S.Gifford-Moore, A.L.Schacht, G.F.Smith, V.Vasudevan, L.L.Zornes, and V.J.Klimkowski (1999).
The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element.
  Bioorg Med Chem Lett, 9, 2767-2772.  
10440994 Y.Zhou, and M.E.Johnson (1999).
Comparative molecular modeling analysis of-5-amidinoindole and benzamidine binding to thrombin and trypsin: specific H-bond formation contributes to high 5-amidinoindole potency and selectivity for thrombin and factor Xa.
  J Mol Recognit, 12, 235-241.  
9736916 A.S.Ripka, and D.H.Rich (1998).
Peptidomimetic design.
  Curr Opin Chem Biol, 2, 441-452.  
9736918 J.A.Shafer (1998).
Cardiovascular chemotherapy: anticoagulants.
  Curr Opin Chem Biol, 2, 458-465.  
  9792427 S.Tada, and J.J.Blow (1998).
The replication licensing system.
  Biol Chem, 379, 941-949.  
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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