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Nat Struct Mol Biol. 2016 Sep;23(9):859-64. doi: 10.1038/nsmb.3280. Epub 2016 Aug 15.

An accurately preorganized IRES RNA structure enables eIF4G capture for initiation of viral translation.

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Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.


Many viruses bypass canonical cap-dependent translation in host cells by using internal ribosomal entry sites (IRESs) in their transcripts; IRESs hijack initiation factors for the assembly of initiation complexes. However, it is currently unknown how IRES RNAs recognize initiation factors that have no endogenous RNA binding partners; in a prominent example, the IRES of encephalomyocarditis virus (EMCV) interacts with the HEAT-1 domain of eukaryotic initiation factor 4G (eIF4G). Here we report the solution structure of the J-K region of this IRES and show that its stems are precisely organized to position protein-recognition bulges. This multisite interaction mechanism operates on an all-or-nothing principle in which all domains are required. This preorganization is accomplished by an 'adjuster module': a pentaloop motif that acts as a dual-sided docking station for base-pair receptors. Because subtle changes in the orientation abrogate protein capture, our study highlights how a viral RNA acquires affinity for a target protein.

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