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PDBsum entry 1d3q

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1d3q
Jmol PyMol
Contents
Protein chains
28 a.a. *
250 a.a. *
12 a.a. *
Ligands
NAG
BT2
Metals
_NA ×2
* Residue conservation analysis
PDB id:
1d3q
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of human alpha thrombin in complex with benzo[b]thiophene inhibitor 2
Structure: Alpha-thrombin. Chain: a. Engineered: yes. Alpha-thrombin. Chain: b. Engineered: yes. Hirugen. Chain: h
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Hexamer (from PQS)
Resolution:
2.90Å     R-factor:   0.167     R-free:   0.228
Authors: N.Y.Chirgadze
Key ref: N.Y.Chirgadze et al. (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. PubMed id: 10739244 DOI: 10.1110/ps.9.1.29
Date:
30-Sep-99     Release date:   04-Oct-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
28 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
250 a.a.
Protein chain
Pfam   ArchSchema ?
P01050  (HIRV1_HIRME) -  Hirudin variant-1
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.
 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  

 

 
DOI no: 10.1110/ps.9.1.29 Protein Sci 9:29-36 (2000)
PubMed id: 10739244  
 
 
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.
N.Y.Chirgadze, D.J.Sall, S.L.Briggs, D.K.Clawson, M.Zhang, G.F.Smith, R.W.Schevitz.
 
  ABSTRACT  
 
The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20150996 Z.Bikadi, and E.Hazai (2009).
Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock.
  J Cheminform, 1, 15.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
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.

 

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