A picornaviral loop-to-loop replication complex |
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| Authors: | Jolyon K Claridge Stephen J Headey John YH Chow Martin Schwalbe Patrick J Edwards Cy M Jeffries Hariprasad Venugopal Jill Trewhella Steven M Pascal |
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| Institution: | aInstitute of Fundamental Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand;bSchool of Molecular and Microbial Biosciences, University of Sydney, NSW 2006, Australia;cDepartment of Chemistry, University of Utah, UT 84112, USA |
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| 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. |
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| Keywords: | NMR SAXS Picornavirus Rhinovirus Replication 3C protease |
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