Structures and stabilization of kinetoplastid-specific split rRNAs revealed by comparing leishmanial and human ribosomes.

Xing Zhang,Hwee L Ng,Jan Mrazek,Ke Ding,Dmitri A Maslov,Mason Lai,Winston Chang,Z Hong Zhou,Otto O Yang,Iris Yu

doi:10.1038/ncomms13223

Xing Zhang, Hwee L Ng + Show 8 more

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https://doi.org/10.1038/ncomms13223

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The recent success in ribosome structure determination by cryoEM has opened the door to defining structural differences between ribosomes of pathogenic organisms and humans and to understand ribosome-targeting antibiotics. Here, by direct electron-counting cryoEM, we have determined the structures of the Leishmania donovani and human ribosomes at 2.9 Å and 3.6 Å, respectively. Our structure of the leishmanial ribosome elucidates the organization of the six fragments of its large subunit rRNA (as opposed to a single 28S rRNA in most eukaryotes, including humans) and reveals atomic details of a unique 20 amino acid extension of the uL13 protein that pins down the ends of three of the rRNA fragments. The structure also fashions many large rRNA expansion segments. Direct comparison of our human and leishmanial ribosome structures at the decoding A-site sheds light on how the bacterial ribosome-targeting drug paromomycin selectively inhibits the eukaryotic L. donovani, but not human, ribosome.

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The recent success in ribosome structure determination by cryo electron microscopy (cryoEM) has opened the door to defining structural differences between ribosomes of pathogenic organisms and humans and to understand ribosome-targeting antibiotics
In the wake of these advancements, the field of ribosome studies has seen an explosion of high-resolution cryoEM ribosome structures[2,3,4,5,6,7], presenting a remarkable opportunity to define the unique structures of components of the L. donovani ribosome, which should provide valuable information about kinetoplastid ribosome biogenesis and may serve as the basis for future identification of antibiotic targets
No highresolution structure is available of a leishmanial ribosome, and the only existing trypanosomal ribosome structures are that of Trypanosoma brucei at 5.57 Å resolution[3] and that of Trypanosoma cruzi at 12 Å resolution[11], both of which lack atomic details of protein–RNA and RNA–RNA interactions needed for understanding the stabilization of fragmented ribosomal RNA (rRNA) and for describing chemical specificity of ribosome-targeting drugs

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The recent success in ribosome structure determination by cryoEM has opened the door to defining structural differences between ribosomes of pathogenic organisms and humans and to understand ribosome-targeting antibiotics. Comparison of the atomic model of the leishmanial ribosome with that of the human ribosome reveals RNA–protein interactions formed among the ends of the split rRNA molecules, as well as significant differences in the arrangement and presence of ribosomal RNA expansion segments, and base-pair features at the decoding A-site relevant to selective inhibition by paromomycin.

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