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Mapping the interactions of selected antibiotics and their Cu2+ complexes with the antigenomic delta ribozyme.
Autorzy
Rok wydania
2013
Czasopismo
Numer woluminu
280
Strony
2652-2664
DOI
10.1111/febs.12257
Kolekcja
Język
Angielski
Typ publikacji
Artykuł
The interactions of selected antibiotics with the trans‐acting antigenomic delta ribozyme were mapped. Ribozyme with two oligonucleotide substrates was used, one uncleavable with deoxycytidine at the cleavage site, mimicking the initial state of ribozyme, and the other with an all‐RNA substrate mimicking, after cleavage, the product state. Mapping was performed with a set of RNA structural probing methods: P b2+ ‐induced cleavage, nuclease digestion, and the selective 2′‐hydroxyl acylation analyzed by primer extension (SHAPE ) approach. The experimental results combined with molecular modeling revealed different binding sites for neomycin B , amikacin and actinomycin D inside the ribozyme structure. Neomycin B , an aminoglycoside antibiotic, which strongly inhibited the catalytic properties of delta ribozyme, was bound to the pocket formed by the P 1 stem, the P 1.1 pseudoknot, and the J 4/2 junction. Amikacin showed less effective binding to the ribozyme catalytic core, resulting in weak inhibition. Complexes of these aminoglycosides with C u2+ ions were bound to the same ribozyme regions, but more effectively, showing lower K d values. On the other hand, the C u2+ complex of the cyclopeptide antibiotic actinonomycin D was preferentially intercalated into the P 2 and the P 4 double‐stranded region, and was three times more potent in ribozyme inhibition than the free antibiotic. In addition, some differences in SHAPE reactivities between the ribozyme forms containing all‐RNA and deoxycytidine‐modified substrates in the J 4/2 region were detected, pointing to different ribozyme conformations before and after the cleavage event.
Słowa kluczowe
antibiotics, delta ribozyme, modeling ofantibiotic–ribozyme interaction, RNAprobing, RNA structure
Adres publiczny
http://dx.doi.org/10.1111/febs.12257
Strona internetowa wydawcy
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