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Title: Apramycin Recognition by the Human Ribosomal Decoding Site

Abstract

Aminoglycoside antibiotics bind specifically to the bacterial ribosomal decoding-site RNA and thereby interfere with fidelity but not efficiency of translation. Apramycin stands out among aminoglycosides for its mechanism of action which is based on blocking translocation and its ability to bind also to the eukaryotic decoding site despite differences in key residues required for apramycin recognition by the bacterial target. To elucidate molecular recognition of the eukaryotic decoding site by apramycin we have determined the crystal structure of an oligoribonucleotide containing the human sequence free and in complex with the antibiotic at 1.5 {angstrom} resolution. The drug binds in the deep groove of the RNA which forms a continuously stacked helix comprising non-canonical C{center_dot}A and G{center_dot}A base pairs and a bulged-out adenine. The binding mode of apramycin at the human decoding-site RNA is distinct from aminoglycoside recognition of the bacterial target, suggesting a molecular basis for the actions of apramycin in eukaryotes and bacteria.

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
929876
Report Number(s):
BNL-80448-2008-JA
TRN: US200822%%1062
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Blood Cells, Molecules, and Diseases; Journal Volume: 38; Journal Issue: 3
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ANTIBIOTICS; BACTERIA; BASES; CHANNELING; CRYSTAL STRUCTURE; DRUGS; EFFICIENCY; HUMAN POPULATIONS; RESIDUES; RNA; TRANSLOCATION; national synchrotron light source

Citation Formats

Hermann,T., Tereshko, V., Skripkin, E., and Patel, D. Apramycin Recognition by the Human Ribosomal Decoding Site. United States: N. p., 2007. Web. doi:10.1016/j.bcmd.2006.11.006.
Hermann,T., Tereshko, V., Skripkin, E., & Patel, D. Apramycin Recognition by the Human Ribosomal Decoding Site. United States. doi:10.1016/j.bcmd.2006.11.006.
Hermann,T., Tereshko, V., Skripkin, E., and Patel, D. Mon . "Apramycin Recognition by the Human Ribosomal Decoding Site". United States. doi:10.1016/j.bcmd.2006.11.006.
@article{osti_929876,
title = {Apramycin Recognition by the Human Ribosomal Decoding Site},
author = {Hermann,T. and Tereshko, V. and Skripkin, E. and Patel, D.},
abstractNote = {Aminoglycoside antibiotics bind specifically to the bacterial ribosomal decoding-site RNA and thereby interfere with fidelity but not efficiency of translation. Apramycin stands out among aminoglycosides for its mechanism of action which is based on blocking translocation and its ability to bind also to the eukaryotic decoding site despite differences in key residues required for apramycin recognition by the bacterial target. To elucidate molecular recognition of the eukaryotic decoding site by apramycin we have determined the crystal structure of an oligoribonucleotide containing the human sequence free and in complex with the antibiotic at 1.5 {angstrom} resolution. The drug binds in the deep groove of the RNA which forms a continuously stacked helix comprising non-canonical C{center_dot}A and G{center_dot}A base pairs and a bulged-out adenine. The binding mode of apramycin at the human decoding-site RNA is distinct from aminoglycoside recognition of the bacterial target, suggesting a molecular basis for the actions of apramycin in eukaryotes and bacteria.},
doi = {10.1016/j.bcmd.2006.11.006},
journal = {Blood Cells, Molecules, and Diseases},
number = 3,
volume = 38,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}