A picornaviral loop-to-loop replication complex

Jolyon K. Claridge, Stephen J. Headey, John Y H Chow, Martin Schwalbe, Patrick J. Edwards, Cy M. Jeffries, Hariprasad Venugopal, Jill Trewhella, Steven M. Pascal

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

Picornaviruses replicate their RNA genomes through a highly conserved mechanism that involves an interaction between the principal viral protease (3Cpro) and the 5′-UTR region of the viral genome. The 3Cpro catalytic site is the target of numerous replication inhibitors. This paper describes the first structural model of a complex between a picornaviral 3Cpro and a region of the 5′-UTR, stem-loop D (SLD). Using human rhinovirus as a model system, we have combined NMR contact information, small-angle X-ray scattering (SAXS) data, and previous mutagenesis results to determine the shape, position and relative orientation of the 3Cpro and SLD components. The results clearly identify a 1:1 binding stoichiometry, with pronounced loops from each molecule providing the key binding determinants for the interaction. Binding between SLD and 3Cpro induces structural changes in the proteolytic active site that is positioned on the opposite side of the protease relative to the RNA/protein interface, suggesting that subtle conformational changes affecting catalytic activity are relayed through the protein.

Original languageEnglish
Pages (from-to)251-262
Number of pages12
JournalJournal of Structural Biology
Volume166
Issue number3
DOIs
Publication statusPublished - Jun 2009
Externally publishedYes

Keywords

  • 3C protease
  • NMR
  • Picornavirus
  • Replication
  • Rhinovirus
  • SAXS

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