Aminoglycoside binding to human and bacterial A-Site rRNA decoding region constructs.
The 16S bacterial ribosomal A-site decoding rRNA region is thought to be the pharmacological target for the aminoglycoside antibiotics. The clinical utility of aminoglycosides could possibly depend on the preferential binding of these drugs to the prokaryotic A-site versus the corresponding A-site from eukaryotes. However, quantitative aminoglycoside binding experiments reported here on prokaryotic and eukaryotic A-site RNA constructs show that there is little in the way of differential binding affinities of aminoglycosides for the two targets. The largest difference in affinity is 4-fold in the case of neomycin, with the prokaryotic A-site construct exhibiting the higher binding affinity. Mutational studies revealed that decoding region constructs retaining elements of non-Watson-Crick (WC) base pairing, specifically bound aminoglycosides with affinities in the muM range. These studies are consistent with the idea that aminoglycoside antibiotics can specifically bind to RNA molecules as long as the latter have non-A form structural elements allowing access of aminoglycosides to the narrow major groove.
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Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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D000465:Algorithms; D000617:Aminoglycosides / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria; D005454:Fluorescence Polarization; D005601:Framycetin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007612:Kanamycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010303:Paromomycin / Q000737:chemistry / Q000494:pharmacology; D012335:RNA, Ribosomal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000737:chemistry / Q000378:metabolism; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014031:Tobramycin / Q000737:chemistry / Q000494:pharmacology
C437523:5-carboxytetramethylrhodamine; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D012335:RNA, Ribosomal; D012336:RNA, Ribosomal, 16S; D012337:RNA, Ribosomal, 18S; C075526:RNA, ribosomal, 12S; D012235:Rhodamines; C001495:bekanamycin; D005601:Framycetin; D007612:Kanamycin; D010303:Paromomycin; D014031:Tobramycin