4g8v | pdb_00004g8v
Crystal structure of Ribonuclease A in complex with 5a
Structural highlights
FunctionRNAS1_BOVIN Endonuclease that catalyzes the cleavage of RNA on the 3' side of pyrimidine nucleotides. Acts on single stranded and double stranded RNA.[1] Publication Abstract from PubMedFive 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 muM 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-[(beta-d-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with K(i)=1.6muM. 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. Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation.,Parmenopoulou V, Chatzileontiadou DS, Manta S, Bougiatioti S, Maragozidis P, Gkaragkouni DN, Kaffesaki E, Kantsadi AL, Skamnaki VT, Zographos SE, Zounpoulakis P, Balatsos NA, Komiotis D, Leonidas DD Bioorg Med Chem. 2012 Oct 16. pii: S0968-0896(12)00801-2. doi:, 10.1016/j.bmc.2012.09.067. PMID:23122937[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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