spacer
spacer

PDBsum entry 4ax9

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
4ax9
Jmol PyMol
Contents
Protein chains
251 a.a.
11 a.a.
28 a.a.
Ligands
N5N
NAG
Metals
_NA ×2
Waters ×217
PDB id:
4ax9
Name: Hydrolase/hydrolase inhibitor
Title: Human thrombin complexed with napsagatran, ro0466240
Structure: Prothrombin. Chain: h. Fragment: thrombin heavy chain, residues 364-620. Synonym: thrombin, coagulation factor ii, activation peptid fragment 1, activation peptide fragment 2, thrombin light thrombin heavy chain. Hirudin variant-1. Chain: i. Fragment: c-terminal domain, residues 55-65.
Source: Homo sapiens. Human. Organism_taxid: 9606. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421. Organ: salivary gland. Organism_taxid: 9606
Resolution:
1.90Å     R-factor:   0.162     R-free:   0.196
Authors: D.W.Banner,A.D'Arcy,F.K.Winkler,K.Hilpert,S.Spinelli,C.Cambi
Key ref: K.Hilpert et al. (1994). Design and synthesis of potent and highly selective thrombin inhibitors. J Med Chem, 37, 3889-3901. PubMed id: 7966150
Date:
11-Jun-12     Release date:   20-Jun-12    
PROCHECK
Go to PROCHECK summary
 Headers
 References

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

 

 
J Med Chem 37:3889-3901 (1994)
PubMed id: 7966150  
 
 
Design and synthesis of potent and highly selective thrombin inhibitors.
K.Hilpert, J.Ackermann, D.W.Banner, A.Gast, K.Gubernator, P.Hadváry, L.Labler, K.Müller, G.Schmid, T.B.Tschopp.
 
  ABSTRACT  
 
Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
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.

 

spacer

spacer