Abstract
The mosquito-borne dengue viruses are widespread human pathogens causing dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, placing 40% of the world's population at risk with no effective treatment. The viral genome is a positive strand RNA that encodes a single polyprotein precursor. Processing of the polyprotein precursor into mature proteins is carried out by the host signal peptidase and by NS3 serine protease, which requires NS2B as a cofactor. We report here the crystal structure of the NS3 serine protease domain at 2.1 A resolution. This structure of the protease combined with modeling of peptide substrates into the active site suggests identities of residues involved in substrate recognition as well as providing a structural basis for several mutational effects on enzyme activity. This structure will be useful for development of specific inhibitors as therapeutics against dengue and other flaviviral proteases.
Highlights
The mosquito-borne dengue viruses are widespread with a type I cap structure at the 5Ј-end and codes for a single human pathogens causing dengue fever, dengue hemor- polyprotein precursor (3,391 amino acid residues for Dengue virus type 2 (Den2)) [5]
Polyprotein precursor into mature proteins is carried out, prM, and E, which are by the host signal peptidase and by NS3 serine protease, components of the virion, and at least seven nonstructural (NS)
In this study we report the structure of the Den2 protease dancy of 4.6) on a Siemens X1000 area detector system at room temperature and processed with XDS [46]
Summary
Modeling of tetrapeptide substrates into the active site indicates that a number of residues that were identified as potential determinants of substrate specificity by sequence alignments do make contacts with the substrate, All derivative data (80% complete to 2.7 Å ) used in phasing were measured from one crystal rotated around the crystallographic b direction to map hkl and h-kl reflections on to the detector simultaneously and in similar geometry, reducing systematic errors in Bijvoet differences. Comparison of the Den protease structure with these HCV protease structures reveals notable differences; for example, the structural zinc binding site and the long hydrophobic NH2-terminal loop of the HCV protease are absent in the Den protease Taken together, this is the Significant improvement to the electron density map calculated with weighted SIRAS phases was obtained using DM [50], and a model of approximately 40% of the protein was built into this map using Bones and O [51].
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