1. Nucleotide-dependent dynamics of the Dengue NS3 helicase.
- Author
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Sarto C, Kaufman SB, Estrin DA, and Arrar M
- Subjects
- Adenosine Triphosphate metabolism, Amino Acid Motifs, Binding Sites, Dengue Virus enzymology, Hydrolysis, Molecular Dynamics Simulation, Phosphates metabolism, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, RNA Helicases chemistry, RNA Helicases metabolism, Serine Endopeptidases chemistry, Serine Endopeptidases metabolism, Thermodynamics, Viral Nonstructural Proteins metabolism, Adenosine Triphosphate chemistry, Dengue Virus chemistry, Phosphates chemistry, Viral Nonstructural Proteins chemistry
- Abstract
Dengue represents a substantial public health burden, particularly in low-resource countries. Non-structural protein 3 (NS3) is a multifunctional protein critical in the virus life cycle and has been identified as a promising anti-viral drug target. Despite recent crystallographic studies of the NS3 helicase domain, only subtle structural nucleotide-dependent differences have been identified, such that its coupled ATPase and helicase activities remain mechanistically unclear. Here we use molecular dynamics simulations to explore the nucleotide-dependent conformational landscape of the Dengue virus NS3 helicase and identify substantial changes in the protein flexibility during the ATP hydrolysis cycle. We relate these changes to the RNA-protein interactions and proposed translocation models for other monomeric helicases. Furthermore, we report a novel open-loop conformation with a likely escape route for P
i after hydrolysis, providing new insight into the conformational changes that underlie the ATPase activity of NS3., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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