Journal of Biological Chemistry
Volume 274, Issue 9, 26 February 1999, Pages 5573-5580
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ENZYMOLOGY
Dengue Virus NS3 Serine Protease: CRYSTAL STRUCTURE AND INSIGHTS INTO INTERACTION OF THE ACTIVE SITE WITH SUBSTRATES BY MOLECULAR MODELING AND STRUCTURAL ANALYSIS OF MUTATIONAL EFFECTS*

https://doi.org/10.1074/jbc.274.9.5573Get rights and content
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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 Å 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.

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*

This work was supported in part by American Cancer Society Grant IRG 204 (to K. M.) and by National Institutes of Health Grant AI-32078 and the Johnson & Johnson Foundation (to R. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 1bef) have been deposited in the Protein Data Bank, Brookhaven National Laboratory, Upton, NY.

Supported in part by a predoctoral fellowship from the Kansas Health Foundation.