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PDBsum entry 1no9

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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1no9
Jmol
Contents
Protein chains
36 a.a. *
253 a.a. *
11 a.a. *
Ligands
NAG
4ND
Waters ×147
* Residue conservation analysis
PDB id:
1no9
Name: Hydrolase/hydrolase inhibitor
Title: Design of weakly basic thrombin inhibitors incorporating nov binding functions: molecular and x-ray crystallographic stu
Structure: Alpha thrombin. Chain: l. Fragment: light chain. Alpha thrombin. Chain: h. Fragment: heavy chain. Hirugen. Chain: i. Fragment: chain i.
Source: Homo sapiens. Human. Organism_taxid: 9606. Other_details: plasma. Synthetic: yes. Hirudo medicinalis. Organism_taxid: 6421
Biol. unit: Trimer (from PQS)
Resolution:
1.90Å     R-factor:   0.183     R-free:   0.204
Authors: G.De Simone,V.Menchise,S.Omaggio,C.Pedone,A.Scozzafava,C.T.S
Key ref:
G.De Simone et al. (2003). Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: molecular and X-ray crystallographic studies. Biochemistry, 42, 9013-9021. PubMed id: 12885234 DOI: 10.1021/bi020512l
Date:
16-Jan-03     Release date:   26-Aug-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
36 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
253 a.a.
Protein chain
Pfam   ArchSchema ?
P01050  (HIRV1_HIRME) -  Hirudin variant-1
Seq:
Struc:
65 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 L, H: 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     catalytic activity     3 terms  

 

 
DOI no: 10.1021/bi020512l Biochemistry 42:9013-9021 (2003)
PubMed id: 12885234  
 
 
Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: molecular and X-ray crystallographic studies.
G.De Simone, V.Menchise, S.Omaggio, C.Pedone, A.Scozzafava, C.T.Supuran.
 
  ABSTRACT  
 
To prepare weakly basic thrombin inhibitors with modified S1 anchoring groups, two series of compounds were synthesized by reaction of guanidine or aminoguanidine with acyl halides and N,N-disubstituted carbamoyl chlorides. pK(a) measurements of these acylated guanidines/aminoguanidines showed a reduced basicity, with pK(a) values in the range of 8.4-8.7. These molecules typically showed inhibition constants in the range of 150-425 nM against thrombin and 360-965 nM against trypsin, even though some bulky derivatives, such as N,N-diphenylcarbamoylguanidine/aminoguanidine and their congeners, showed much stronger thrombin inhibitory activity, with inhibition constants in the range of 24-42 nM. Unexpectedly, very long incubation times with both proteases revealed that aminoguanidine derivatives behaved as irreversible inhibitors. To assess the molecular basis responsible for the high affinity observed for these molecules toward thrombin, the crystal structure of the thrombin-hirugen-N,N-diphenylcarbamoylaminoguanidine complex has been solved at 1.90 A resolution. The structural analysis of the complex revealed an unexpected interaction mode with the protease, resulting in an N,N-diphenylcarbamoyl intermediate covalently bound to the catalytic serine as a consequence of its hydrolysis together with the release of the aminoguanidine moiety. Surprisingly, in this covalent adduct a phenyl group was found in the S1 specificity pocket, which usually recognizes positively charged residues. These findings provide new insights in the design of low basicity serine protease inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
18573080 V.N.Uversky, C.J.Oldfield, and A.K.Dunker (2008).
Intrinsically disordered proteins in human diseases: introducing the D2 concept.
  Annu Rev Biophys, 37, 215-246.  
16428384 L.A.Bush, R.W.Nelson, and E.Di Cera (2006).
Murine thrombin lacks Na+ activation but retains high catalytic activity.
  J Biol Chem, 281, 7183-7188.  
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