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| Title | Structural basis for RNA synthesis and inhibition of the orthobunyavirus polymerase. |
|---|---|
| Journal, issue, pages | Nat Commun, Year 2026 |
| Publish date | May 15, 2026 |
 Authors | Jingjing Tang / Wenhua Kuang / Wei Chen / Hao Wu / Yong Wang / Jinyue Li / Zhiming Yuan / Han Xia / Haiyan Zhao / Zengqin Deng /  |
| PubMed Abstract | Orthobunyaviruses are segmented negative-sense RNA viruses that encompass several life-threatening human and animal pathogens. However, no licensed antivirals are currently available. The viral RNA- ...Orthobunyaviruses are segmented negative-sense RNA viruses that encompass several life-threatening human and animal pathogens. However, no licensed antivirals are currently available. The viral RNA-dependent RNA polymerase (RdRp) is a multi-domain enzyme critical for genome replication and transcription, representing a promising target for antiviral drug development. Here, we establish robust in vitro enzymatic activity assays for the Ebinur Lake virus (EBIV) polymerase and identify suramin, a century-old drug, as an inhibitor of EBIV polymerase. We further determine cryo-EM structures of the EBIV polymerase in apo, elongation, and suramin-bound states. These structures reveal conformational rearrangements of the polymerase during RNA synthesis, including conformational transitions of the prime-and-realign (PR) loop and a unique β-hairpin that bridges the zinc-binding domain (ZBD) to the RdRp core. The structural observations are correlated with in vitro enzymatic activity and cell-based minireplicon assays. The suramin-bound structure reveals two distinct inhibitory binding sites. One site sterically clashes with the vRNA promoter. The other site directly blocks RNA template strand binding, thereby inhibiting polymerase activity. These findings advance our understanding of orthobunyavirus RNA synthesis mechanisms and offer a structural framework for the rational design and optimization of antiviral drugs. |
 External links | Nat Commun / PubMed:42140913 |
| Methods | EM (single particle) |
| Resolution | 3.0 - 3.55 Å |
| Structure data | EMDB-65295, PDB-9vs3: EMDB-65296, PDB-9vs4: EMDB-65297, PDB-9vs5: |
| Chemicals |  ChemComp-SVR: |
| Source |
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 Keywords | VIRAL PROTEIN / polymerase / suramin / VIRAL PROTEIN/RNA / elongation complex / L protein / RNA / VIRAL PROTEIN-RNA complex |
ebinur lake virus
Pipistrellus nathusii (Nathusius's pipistrelle)