Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 16, Issue 8, Pages 4466-4470Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.02.056
Keywords
aminoglycoside; RNA; antitermination; T box; binding; inhibition
Funding
- NIGMS NIH HHS [R01 GM061048-02, R01 GM061048-05, R01 GM061048, R01 GM061048-01A1, GM61048, R01 GM061048-03, R01 GM061048-04] Funding Source: Medline
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The T box transcription antitermination mechanism regulates the expression of unique genes in many Gram-positive bacteria by responding, in a magnesium-dependent manner, to uncharged cognate tRNA base pairing with an antiterminator RNA element and other regions of the 5'-untranslated region. Model T box antiterminator RNA is known to bind aminoglycosides, ligands that typically bind RNA in divalent metal ion-binding sites. In this study, enzymatic footprinting and spectroscopic assays were used to identify and characterize the binding site of neomycin B to an antiterminator model RNA. Neomycin B binds the antiterminator bulge nucleotides in an electrostatic-dependent manner and displaces 3-4 monovalent cations, indicating that the antiterminator likely contains a divalent metal ion-binding site. Neomycin B facilitates rather than inhibits tRNA binding indicating that bulge-targeted inhibitors that bind the antiterminator via non-electrostatic interactions may be the more optimal candidates for antiterminator-targeted ligand design. (C) 2008 Elsevier Ltd. All rights reserved.
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