Structure
Volume 19, Issue 10, 12 October 2011, Pages 1456-1466
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Article
Crystal Structure of the HCV IRES Central Domain Reveals Strategy for Start-Codon Positioning

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Summary

Translation of hepatitis C viral proteins requires an internal ribosome entry site (IRES) located in the 5′ untranslated region of the viral mRNA. The core domain of the hepatitis C virus (HCV) IRES contains a four-way helical junction that is integrated within a predicted pseudoknot. This domain is required for positioning the mRNA start codon correctly on the 40S ribosomal subunit during translation initiation. Here, we present the crystal structure of this RNA, revealing a complex double-pseudoknot fold that establishes the alignment of two helical elements on either side of the four-helix junction. The conformation of this core domain constrains the open reading frame's orientation for positioning on the 40S ribosomal subunit. This structure, representing the last major domain of HCV-like IRESs to be determined at near-atomic resolution, provides the basis for a comprehensive cryoelectron microscopy-guided model of the intact HCV IRES and its interaction with 40S ribosomal subunits.

Highlights

► Crystal structure of the most complex HCV IRES domain reveals its functional core ► A tertiary base pair creates a double pseudoknot encompassing a four-helix junction ► Final domain to be solved facilitates comprehensive IRES model bound to 40S subunit ► Orientation of two helical elements directs start-codon positioning by the IRES

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5

Present address: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA

6

Present address: Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA