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Journal of Virology, January 2007, p. 650-668, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01327-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Structure of the 5' Nontranslated Region of the Coxsackievirus B3 Genome: Chemical Modification and Comparative Sequence Analysis

Jennifer M. Bailey and William E. Tapprich^*

Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68182-0040

Received 23 June 2006/ Accepted 20 October 2006

Coxsackievirus B3 (CVB3) is a picornavirus which causes myocarditis and pancreatitis and may play a role in type I diabetes. The viral genome is a single 7,400-nucleotide polyadenylated RNA encoding 11 proteins in a single open reading frame. The 5' end of the viral genome contains a highly structured nontranslated region (5'NTR) which folds to form an internal ribosome entry site (IRES) as well as structures responsible for genome replication, both of which are critical for virulence. A structural model of the CVB3 5'NTR, generated primarily by comparative sequence analysis and energy minimization, shows seven domains (I to VII). While this model provides a preliminary basis for structural analysis, the model lacks comprehensive experimental validation. Here we provide experimental evidence from chemical modification analysis to determine the structure of the CVB3 5'NTR. Chemical probing results show that the theoretical model for the CVB3 5'NTR is largely, but not completely, supported experimentally. In combination with our chemical probing data, we have used the RNASTRUCTURE algorithm and sequence comparison of 105 enterovirus sequences to provide evidence for novel secondary and tertiary interactions. A comprehensive examination of secondary structure is discussed, along with new evidence for tertiary interactions. These include a loop E motif in domain III and a long-range pairing interaction that links domain II to domain V. The results of our work provide mechanistic insight into key functional elements in the cloverleaf and IRES, thereby establishing a base of structural information from which to interpret experiments with CVB3 and other picornaviruses.

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* Corresponding author. Mailing address: Biology Department, University of Nebraska at Omaha, 6001 Dodge St, Omaha, NE 68182. Phone: (402) 554-3380. Fax: (402) 554-3532. E-mail: wtapprich{at}mail.unomaha.edu.

Published ahead of print on 1 November 2006.

Present address: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198.

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Journal of Virology, January 2007, p. 650-668, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01327-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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