A mechanism for initiating RNA-dependent RNA polymerization

Sarah J. Butcher, Jonathan M. Grimes, Eugeny V. Makeyev, Dennis H. Bamford and David I. Stuart ()
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Sarah J. Butcher: University of Helsinki
Jonathan M. Grimes: The Henry Wellcome Building for Genomic Medicine, Oxford University
Eugeny V. Makeyev: University of Helsinki
Dennis H. Bamford: University of Helsinki
David I. Stuart: The Henry Wellcome Building for Genomic Medicine, Oxford University

Nature, 2001, vol. 410, issue 6825, 235-240

Abstract: Abstract In most RNA viruses, genome replication and transcription are catalysed by a viral RNA-dependent RNA polymerase. Double-stranded RNA viruses perform these operations in a capsid (the polymerase complex), using an enzyme that can read both single- and double-stranded RNA. Structures have been solved for such viral capsids, but they do not resolve the polymerase subunits in any detail1,2. Here we show that the 2 Å resolution X-ray structure of the active polymerase subunit from the double-stranded RNA bacteriophage φ6 (refs 3, 4) is highly similar to that of the polymerase of hepatitis C virus, providing an evolutionary link between double-stranded RNA viruses and flaviviruses. By crystal soaking and co-crystallization, we determined a number of other structures, including complexes with oligonucleotide and/or nucleoside triphosphates (NTPs), that suggest a mechanism by which the incoming double-stranded RNA is opened up to feed the template through to the active site, while the substrates enter by another route. The template strand initially overshoots, locking into a specificity pocket, and then, in the presence of cognate NTPs, reverses to form the initiation complex; this process engages two NTPs, one of which acts with the carboxy-terminal domain of the protein to prime the reaction. Our results provide a working model for the initiation of replication and transcription.

Date: 2001
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DOI: 10.1038/35065653

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