4G8Y

Crystal structure of Ribonuclease A in complex with 5b


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation.

Parmenopoulou, V.Chatzileontiadou, D.S.Manta, S.Bougiatioti, S.Maragozidis, P.Gkaragkouni, D.N.Kaffesaki, E.Kantsadi, A.L.Skamnaki, V.T.Zographos, S.E.Zounpoulakis, P.Balatsos, N.A.Komiotis, D.Leonidas, D.D.

(2012) Bioorg Med Chem 20: 7184-7193

  • DOI: https://doi.org/10.1016/j.bmc.2012.09.067
  • Primary Citation of Related Structures:  
    4G8V, 4G8Y, 4G90

  • PubMed 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) = 1.6 μM. 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.


  • Organizational Affiliation

    Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos St., 41221 Larissa, Greece.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ribonuclease pancreatic
A, B
124Bos taurusMutation(s): 0 
EC: 3.1.27.5
UniProt
Find proteins for P61823 (Bos taurus)
Explore P61823 
Go to UniProtKB:  P61823
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61823
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0FT
Query on 0FT

Download Ideal Coordinates CCD File 
C [auth A]1-{[1-(alpha-L-arabinofuranosyl)-1H-1,2,3-triazol-4-yl]methyl}-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
C13 H17 N5 O6
FVDUYFCPFLONHE-UXCLJVHYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0FT PDBBind:  4G8Y Ki: 2.58e+4 (nM) from 1 assay(s)
Binding MOAD:  4G8Y Ki: 2.58e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 100.301α = 90
b = 32.672β = 89.35
c = 72.38γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
REFMACrefinement
CrysalisProdata collection
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-21
    Type: Initial release
  • Version 1.1: 2012-12-12
    Changes: Database references
  • Version 1.2: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description