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PDBsum entry 2c8y

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
2c8y
Jmol PyMol
Contents
Protein chains
29 a.a. *
251 a.a. *
11 a.a. *
Ligands
DMS ×3
C3M
Metals
_NA
Waters ×298
* Residue conservation analysis
PDB id:
2c8y
Name: Hydrolase/hydrolase inhibitor
Title: Thrombin inhibitors
Structure: Thrombin light chain. Chain: a. Fragment: fragment alpha thrombin, residues 328-363. Thrombin heavy chain. Chain: b. Fragment: fragment alpha thrombin, residues 364-622. Hirudin variant-2. Chain: i. Fragment: peptide fragment of hirudin, residues 61-72.
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood plasma. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Trimer (from PDB file)
Resolution:
2.20Å     R-factor:   0.188     R-free:   0.259
Authors: N.Howard,C.Abell,W.Blakemore,R.Carr,G.Chessari,M.Congreve,S. H.Jhoti,C.W.Murray,L.C.A.Seavers,R.L.M.Van Montfort
Key ref: N.Howard et al. (2006). Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors. J Med Chem, 49, 1346-1355. PubMed id: 16480269 DOI: 10.1021/jm050850v
Date:
08-Dec-05     Release date:   04-Jul-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
29 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
251 a.a.
Protein chain
Pfam   ArchSchema ?
P09945  (HIRV2_HIRME) -  Hirudin variant-2 (Fragment)
Seq:
Struc:
72 a.a.
11 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: 10.1021/jm050850v J Med Chem 49:1346-1355 (2006)
PubMed id: 16480269  
 
 
Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors.
N.Howard, C.Abell, W.Blakemore, G.Chessari, M.Congreve, S.Howard, H.Jhoti, C.W.Murray, L.C.Seavers, R.L.van Montfort.
 
  ABSTRACT  
 
The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20223699 A.G.Coyne, D.E.Scott, and C.Abell (2010).
Drugging challenging targets using fragment-based approaches.
  Curr Opin Chem Biol, 14, 299-307.  
20190516 D.Tanaka (2010).
[Fragment-based drug discovery: concept and aim].
  Yakugaku Zasshi, 130, 315-323.  
20665758 J.J.Barker, O.Barker, S.M.Courtney, M.Gardiner, T.Hesterkamp, O.Ichihara, O.Mather, C.A.Montalbetti, A.Müller, M.Varasi, M.Whittaker, and C.J.Yarnold (2010).
Discovery of a novel Hsp90 inhibitor by fragment linking.
  ChemMedChem, 5, 1697-1700.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
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.  
18612831 D.C.Thompson, R.A.Denny, R.Nilakantan, C.Humblet, D.Joseph-McCarthy, and E.Feyfant (2008).
CONFIRM: connecting fragments found in receptor molecules.
  J Comput Aided Mol Des, 22, 761-772.  
18412174 P.M.Fischer (2008).
Computational chemistry approaches to drug discovery in signal transduction.
  Biotechnol J, 3, 452-470.  
17524728 A.A.Shelat, and R.K.Guy (2007).
The interdependence between screening methods and screening libraries.
  Curr Opin Chem Biol, 11, 244-251.  
17851109 H.Jhoti, A.Cleasby, M.Verdonk, and G.Williams (2007).
Fragment-based screening using X-ray crystallography and NMR spectroscopy.
  Curr Opin Chem Biol, 11, 485-493.  
17084612 D.A.Erlanson (2006).
Fragment-based lead discovery: a chemical update.
  Curr Opin Biotechnol, 17, 643-652.  
16902937 W.T.Mooij, M.J.Hartshorn, I.J.Tickle, A.J.Sharff, M.L.Verdonk, and H.Jhoti (2006).
Automated protein-ligand crystallography for structure-based drug design.
  ChemMedChem, 1, 827-838.  
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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