4G8V

Crystal structure of Ribonuclease A in complex with 5a

Summary for 4G8V

• Entry DOI: 10.2210/pdb4g8v/pdb
• Related: 4G8Y 4G90
• Descriptor: Ribonuclease pancreatic, 1-{[1-(alpha-L-arabinofuranosyl)-1H-1,2,3-triazol-4-yl]methyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine (3 entities in total)
• Functional Keywords: nuclease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bos taurus (bovine,cow,domestic cattle,domestic cow)
• Total number of polymer chains: 2
• Total formula weight: 27741.93

Authors

Chatzileontiadou, D.S.M.,Kantsadi, A.L.,Leonidas, D.D. (deposition date: 2012-07-23, release date: 2012-11-21, Last modification date: 2024-10-09)

Primary citation

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.
Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation.
Bioorg.Med.Chem., 20:7184-7193, 2012

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.

PubMed: 23122937
DOI: 10.1016/j.bmc.2012.09.067

Experimental method

X-RAY DIFFRACTION (1.7 Å)