Another HCV target if the current ones are not sufficient for an all-oral treatment
Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches
Sergey M. Dibrov a, Kejia Ding a, Nicholas D. Brunn a, Matthew A. Parker b, B. Mikael Bergdahl b, David L. Wyles c, and Thomas Hermann a
Author Affiliations
a Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093;
b Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182; and
c Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093
Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved February 6, 2012 (received for review November 13, 2011)
Abstract
The internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is essential for the initiation of viral protein synthesis. IRES domains adopt well-defined folds that are potential targets for antiviral translation inhibitors. We have determined the three-dimensional structure of the IRES subdomain IIa in complex with a benzimidazole translation inhibitor at 2.2 Å resolution. Comparison to the structure of the unbound RNA in conjunction with studies of inhibitor binding to the target in solution demonstrate that the RNA undergoes a dramatic ligand-induced conformational adaptation to form a deep pocket that resembles the substrate binding sites in riboswitches. The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain IIa holds promise for the development of unique anti-HCV drugs with a high barrier to resistance.
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