Dataset Information

Structural analyses clarify the complex control of mistranslation by tRNA synthetases.

ABSTRACT: Proteins are precisely assembled with amino acids by matching the anticodons of charged transfer RNAs to nucleotide triplets in mRNA sequences. Accurate translation depends on the specific coupling of cognate amino acids and tRNAs - a step carried out by aminoacyl-tRNA synthetases (aaRSs) and that generates the genetic code. Owing to their intrinsic similarity, aaRSs developed highly differentiated structures to discriminate between amino acids at the active site for aminoacylation. Because this discrimination is not sufficient to prevent toxic mistranslation, aaRSs developed separate structures to further refine recognition by proofreading. From comprehensive structural studies on aaRSs, many of the molecular details have been elucidated for the recognition of cognate amino acids and for the misactivation and editing of noncognate amino acids, Here we review recent advances in the structural description of the binding, activation and editing of amino acids, which collectively reveal many aspects of the fine-tuned systems that resulted in a robust and universal genetic code.

SUBMITTER: Guo M

PROVIDER: S-EPMC3288634 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural analyses clarify the complex control of mistranslation by tRNA synthetases.

Guo Min M Schimmel Paul P

Current opinion in structural biology 20111210 1

Proteins are precisely assembled with amino acids by matching the anticodons of charged transfer RNAs to nucleotide triplets in mRNA sequences. Accurate translation depends on the specific coupling of cognate amino acids and tRNAs - a step carried out by aminoacyl-tRNA synthetases (aaRSs) and that generates the genetic code. Owing to their intrinsic similarity, aaRSs developed highly differentiated structures to discriminate between amino acids at the active site for aminoacylation. Because this ...[more]

PMID: 22155179

Similar Datasets

Project description:BackgroundHelminth infections affect ~ 60% of the human population that lives in tropical and subtropical regions worldwide. These infections result in diseases like schistosomiasis, lymphatic filariasis, river blindness and echinococcosis. Here we provide a comprehensive computational analysis of the aminoacyl tRNA synthetase (aaRS) enzyme family from 27 human-infecting helminths. Our analyses support the idea that several helminth aaRSs can be targeted for drug repurposing or for development of new drugs. For experimental validation, we focused on Onchocerciasis (also known as "river blindness"), a filarial vector-borne disease that is prevalent in Africa and Latin America. We show that halofuginone (HF) can act as a potent inhibitor of Onchocerca volvulus prolyl tRNA synthetase (OvPRS).ResultsThe conserved enzyme family of aaRSs has been validated as druggable targets in numerous eukaryotic parasites. We thus embarked on assessing aaRSs from the genomes of 27 helminths that cause infections in humans. In order to delineate the distribution of aaRSs per genome we utilized Hidden Markov Models of aaRS catalytic domains to identify all orthologues. We note that Fasciola hepatica genome encodes the highest number of aaRS-like proteins (69) whereas Taenia asiatica has the lowest count (32). The number of genes for any particular aaRS-like protein varies from 1 to 8 in these 27 studied helminths. Sequence alignments of helminth-encoded lysyl, prolyl, leucyl and threonyl tRNA synthetases suggest that various known aaRS inhibitors like Cladosporin, Halofuginone, Benzoborale and Borrelidin may be of utility against helminths. The recombinantly expressed Onchocerca volvulus PRS was used as proof of concept for targeting aaRS with drug-like molecules like HF.ConclusionsSystematic analysis of unique subdomains within helminth aaRSs reveals the presence of a number of non-canonical domains like PAC3, Utp-14, Pex2_Pex12 fused to catalytic domains in the predicted helminth aaRSs. We have established a platform for biochemical validation of a large number of helminth aaRSs that can be targeted using available inhibitors to jump-start drug repurposing against human helminths.

Dataset Information

Structural analyses clarify the complex control of mistranslation by tRNA synthetases.

Publications

Structural analyses clarify the complex control of mistranslation by tRNA synthetases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets