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Review
. 2018;15(4-5):667-677.
doi: 10.1080/15476286.2018.1429879. Epub 2018 Feb 2.

Drugging tRNA aminoacylation

Joanne M Ho  1 , Erol Bakkalbasi  2 , Dieter Söll  3   4 , Corwin A Miller  2
Affiliations
Review

Drugging tRNA aminoacylation

Joanne M Ho et al. RNA Biol. 2018.

Abstract

Inhibition of tRNA aminoacylation has proven to be an effective antimicrobial strategy, impeding an essential step of protein synthesis. Mupirocin, the well-known selective inhibitor of bacterial isoleucyl-tRNA synthetase, is one of three aminoacylation inhibitors now approved for human or animal use. However, design of novel aminoacylation inhibitors is complicated by the steadfast requirement to avoid off-target inhibition of protein synthesis in human cells. Here we review available data regarding known aminoacylation inhibitors as well as key amino-acid residues in aminoacyl-tRNA synthetases (aaRSs) and nucleotides in tRNA that determine the specificity and strength of the aaRS-tRNA interaction. Unlike most ligand-protein interactions, the aaRS-tRNA recognition interaction represents coevolution of both the tRNA and aaRS structures to conserve the specificity of aminoacylation. This property means that many determinants of tRNA recognition in pathogens have diverged from those of humans-a phenomenon that provides a valuable source of data for antimicrobial drug development.

Keywords: Aminoacylation; aminoacyl tRNA synthetases; antibiotic targets; antibiotics; antimicrobials; drug development; drug targets; transfer RNA; translation inhibitors.

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Figures

Scheme 1.
Scheme 1.
Figure 1.
Figure 1.
Druggable regions for inhibition of aminoacylation. Examples of drugs targeting each region of either the aaRS enzyme of tRNA substrate are shown. Acceptor stem and anticodon tRNA regions (highlighted in red) are frequently strong determinants for aaRS recognition. Notable residues comprising the anticodon (N34, N35, N36), CCA-tail (A76, C75, C74) and discriminator base (N73) are also shown. AaRS regions involved in tRNA recognition are also depicted, including the tRNA, ATP, and amino acid sites in the catalytic domain, as well as the anticodon recognition region (shown in red) of the anticodon binding domain.
Figure 2.
Figure 2.
X-ray crystal structure of Neomycin B bound to tRNAPhe. Shown at 2.6A° resolution (PDB file 1I9V), Neomycin B occupies a binding cleft on tRNAPhe one full helical turn above the anticodon stem-loop. Interactions within 3.5 Å include nucleotides 20, 44, and 45, which are represented by dashed yellow lines.
See this image and copyright information in PMC

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