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Journal of Virology, October 2008, p. 9458-9464, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00647-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Crystal Structure of Coxsackievirus B3 3Dpol Highlights the Functional Importance of Residue 5 in Picornavirus Polymerases {triangledown}

Grace Campagnola, Mark Weygandt, Kirsten Scoggin, and Olve Peersen*

Department of Biochemistry and Molecular Biology, 1870 Campus Delivery, Colorado State University, Fort Collins, Colorado 80523-1870

Received 22 March 2008/ Accepted 10 July 2008

The crystal structure of the coxsackievirus B3 polymerase has been solved at 2.25-Å resolution and is shown to be highly homologous to polymerases from poliovirus, rhinovirus, and foot-and-mouth disease viruses. Together, these structures highlight several conserved structural elements in picornaviral polymerases, including a proteolytic activation-dependent N-terminal structure that is essential for full activity. Interestingly, a comparison of all of the picornaviral polymerase structures shows an unusual conformation for residue 5, which is always located at a distortion in the β-strand composed of residues 1 to 8. In our earlier structure of the poliovirus polymerase, we attributed this conformation to a crystal packing artifact, but the observation that this conformation is conserved among picornaviruses led us to examine the role of this residue in further detail. Here we use coxsackievirus polymerase to show that elongation activity correlates with the hydrophobicity of residue 5 and, surprisingly, more hydrophobic residues result in higher activity. Based on structural analysis, we propose that this residue becomes buried during the nucleotide repositioning step that occurs prior to phosphoryl transfer. We present a model in which the buried N terminus observed in all picornaviral polymerases is essential for stabilizing the structure during this conformational change.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, 1870 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1870. Phone: (970) 491-0433. Fax: (970) 491-0494. E-mail: Olve.Peersen{at}ColoState.edu

{triangledown} Published ahead of print on 16 July 2008.

Journal of Virology, October 2008, p. 9458-9464, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00647-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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