Aminoglycoside antibiotics bound to aminoglycoside-detoxifying enzymes and RNA adopt similar conformations |
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Authors: | James R Cox Drew R Ekman Enrico L DiGiammarino Ayça Akal-Strader Engin H Serpersu |
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Institution: | (1) Murray State University, 456 Blackburn Science Bldg., 4207-3346 Murray, KY;(2) Department of Structural Biology, St. Jude Children’s Research Hospital, 332 N. Lauderdate, 38105 Memphis, TN;(3) Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Walters Life Sciences building, M407, 37996-0840 Knoxville, TN |
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Abstract: | Conformations of ribostamycin and isepamicin, aminoglycoside antibiotics, bound to an aminoglycoside antibiotic, 3′-phosphotransferase,
were determined by transferred nuclear Overhauser effect spectroscopy and molecular modeling. Two major conformers of enzyme-bound
ribostamycin, a neomycin-group aminoglyeoside were observed. The 3′- and 5″-OH groups (reactive hydroxyl groups) in the conformers
are placed in approximate locations. One of the conformers is similar to the structure of paromomycin bound to a 27-nucleotide
piece of ribosomal RNA that represents the A-site of the small ribosomal subunit, where rings A and C are in an orthogonal
arrangement.
Isepamicin, a kanamycin-group aminoglycoside antibiotic, also showed two major enzyme-bound conformations. Both conformations
were similar to those observed for bound isepamicin in the active site of an aminoglycoside(6′)-acetyl transferase-Ii. Conformations
of other RNA-bound kanamycin-group aminoglycosides were also similar to the enzyme-bound conformations of isepamicin. These
observations suggest that aminoglycosides may adopt similar conformations when bound to RNA and protein targets. This may
have significant implications in the design of enzyme inhibitors and/or antibiotics. |
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Keywords: | Aminoglycosides antibiotics antibiotic resistance nuclear magnetic resonance (NMR) antibiotic structure aminoglycoside detoxification substrate conformation ribostamycin isepamicin |
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