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Structures of dengue virus RNA replicase complexes
Takuo Osawa1, Mari Aoki1, Haruhiko Ehara1
1Laboratory for Transcription Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Molecular Cell
|July 21, 2023
Summary
Dengue virus (DENV) replication mechanisms were elucidated using cryo-EM. Structures reveal how viral proteins NS5 and NS3 interact with the viral RNA
Area of Science:
- Virology
- Structural Biology
- Molecular Biology
Background:
- Dengue virus (DENV), a flavivirus, causes significant global health issues.
- DENV replication relies on its 5'-capped positive-sense RNA genome and a unique 5'-stem-loop structure (SLA).
- The viral proteins NS5 and NS3 are crucial for DENV genome replication, but their cooperative mechanisms remain poorly understood.
Purpose of the Study:
- To determine the structural basis of DENV genome replication.
- To elucidate the roles of NS5, NS3, and SLA in viral RNA replication and 5' capping.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of key DENV replication complexes.
- The structures of SLA-bound NS5 (PC), NS3-bound PC (PC-NS3), and an RNA-elongating NS5-NS3 complex (EC) were resolved.
Main Results:
- The structure of PC shows SLA bridging NS5 methyltransferase and RNA-dependent RNA polymerase domains.
- In the EC, the NS3 helicase domain displaces SLA.
- Both SLA and NS3 bind to sites overlapping with human STAT2.
Conclusions:
- These structures reveal the dynamic interplay of SLA, NS5, and NS3 during DENV replication.
- The findings illuminate critical steps: SLA-dependent initiation, processive elongation, and 5' capping.
- This structural insight provides a foundation for developing antiviral strategies against flaviviruses.
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