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PDBsum entry 4g8y

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protein ligands links
Hydrolase/hydrolase inhibitor PDB id
4g8y
Jmol
Contents
Protein chains
124 a.a.
Ligands
0FT
Waters ×246
PDB id:
4g8y
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of ribonuclease a in complex with 5b
Structure: Ribonuclease pancreatic. Chain: a, b. Synonym: rnase 1, rnase a. Ec: 3.1.27.5
Source: Bos taurus. Bovine,cow,domestic cattle,domestic cow. Organism_taxid: 9913. Tissue: pancreas
Resolution:
1.80Å     R-factor:   0.202     R-free:   0.257
Authors: D.S.M.Chatzileontiadou,A.L.Kantsadi,D.D.Leonidas
Key ref: V.Parmenopoulou et al. (2012). Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation. Bioorg Med Chem, 20, 7184-7193. PubMed id: 23122937 DOI: 10.1016/j.bmc.2012.09.067
Date:
23-Jul-12     Release date:   21-Nov-12    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P61823  (RNAS1_BOVIN) -  Ribonuclease pancreatic
Seq:
Struc:
150 a.a.
124 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.1.27.5  - Pancreatic ribonuclease.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Endonucleolytic cleavage to nucleoside 3'-phosphates and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     metabolic process   3 terms 
  Biochemical function     nucleic acid binding     7 terms  

 

 
DOI no: 10.1016/j.bmc.2012.09.067 Bioorg Med Chem 20:7184-7193 (2012)
PubMed id: 23122937  
 
 
Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation.
V.Parmenopoulou, D.S.Chatzileontiadou, S.Manta, S.Bougiatioti, P.Maragozidis, D.N.Gkaragkouni, E.Kaffesaki, A.L.Kantsadi, V.T.Skamnaki, S.E.Zographos, P.Zounpoulakis, N.A.Balatsos, D.Komiotis, D.D.Leonidas.
 
  ABSTRACT  
 
Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low μM inhibition constant (K(i)) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(β-d-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with K(i)=1.6μM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1) subsite while the triazole moiety binds at the main subsite P(1), where P-O5' bond cleavage occurs, and the ribose at the interface between subsites P(1) and P(0) exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential.