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Bacterial Artificial Chromosomes: A Functional Genomics Tool for the Study of Positive-strand RNA Viruses
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Structural Dynamics of the Dengue Virus Non-structural 5 (NS5) Interactions with Promoter Stem Loop A (SLA)
Juliet O Obi1, Kyle C Kihn1, Linfah McQueen1
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201, USA.
Biorxiv : the Preprint Server for Biology
|December 16, 2024
Summary
Dengue virus NS5 protein interacts with stem-loop A promoter, crucial for viral RNA synthesis. Understanding its conformational dynamics aids antiviral drug development targeting dengue NS5.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- The dengue virus (DENV) NS5 protein is essential for viral RNA synthesis and a key target for antiviral therapies.
- NS5 interacts with the 5'-UTR stem-loop A (SLA) promoter, initiating viral genome replication.
Purpose of the Study:
- To elucidate the structural dynamics and molecular details of the DENV serotype 2 NS5 (DENV2 NS5) and SLA interaction.
- To investigate SLA-induced conformational changes in DENV2 NS5.
Main Methods:
- Surface plasmon resonance (SPR)
- Hydrogen-deuterium exchange mass spectrometry (HDX-MS)
- Computational modeling
- Cryo-electron microscopy (cryo-EM) single particle analysis
Main Results:
- DENV2 NS5 binds SLA in a closed conformation with interdomain cooperation between methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains.
- HDX-MS revealed SLA-induced conformational changes in both MTase and RdRp domains of DENV2 NS5.
- The cryo-EM structure provided the first visualization of the DENV2 NS5-SLA complex, showing a conserved binding mode across DENV serotypes.
Conclusions:
- The study enhances understanding of dengue NS5's conformational dynamics during SLA binding.
- These findings support the development of antiviral strategies targeting specific conformational states of dengue NS5.
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