Structural insights into the RNA-dependent RNA polymerase complexes from highly pathogenic Marburg and Ebola viruses

Guobao Li, Tianjiao Du, Jiening Wang, Kaiyue Jie, Zhuolu Ren, Xiaokang Zhang, Long Zhang, Shan Wu () and Heng Ru ()
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Guobao Li: Zhejiang University
Tianjiao Du: Zhejiang University
Jiening Wang: Hubei University
Kaiyue Jie: Zhejiang University
Zhuolu Ren: Zhejiang University
Xiaokang Zhang: Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions
Long Zhang: Zhejiang University
Shan Wu: Hubei University
Heng Ru: Zhejiang University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The Ebola and the Marburg viruses belong to the Filoviridae family, a group of filamentous, single-stranded, negative-sensed RNA viruses. Upon infection, uncontrolled propagation of the Ebola and the Marburg viruses causes severe hemorrhagic fevers with high mortality rates. The replication and transcription of viral genomes are mediated by a polymerase complex consisting of two proteins: L and its cofactor VP35. However, the molecular mechanism of filovirus RNA synthesis remains understudied due to the lack of high-resolution structures of L and VP35 complexes from these viruses. Here, we present the cryo-EM structures of the polymerase complexes for the Marburg virus and the Ebola virus at 2.7 Å and 3.1 Å resolutions respectively. Despite the similar assembly and overall structures between these two viruses, we identify virus-specific L–VP35 interactions. Our data show that intergeneric exchange of VP35 would diminish these interactions and prevent the formation of a functional chimeric polymerase complex between L protein and heterologous VP35. Additionally, we identify a contracted conformation of the Ebola virus polymerase structure, revealing the structural dynamics of the polymerase during RNA synthesis. These insights enhance our understanding of filovirus RNA synthesis mechanisms and may facilitate the development of antiviral drugs targeting filovirus polymerase.

Date: 2025
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DOI: 10.1038/s41467-025-58308-1

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