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  3. Cryo-EM structures of Nipah virus polymerase complex reveal highly varied interactions between L and P proteins among paramyxoviruses

Cryo-EM structures of Nipah virus polymerase complex reveal highly varied interactions between L and P proteins among paramyxoviruses

  • Protein Cell. 2025 Aug 7;16(8):705-723. doi: 10.1093/procel/pwaf014.
Lu Xue 1,  Tiancai Chang 1 2,  Jiacheng Gui 1 3,  Zimu Li 1 2 4,  Heyu Zhao 1 3,  Binqian Zou 1 2,  Junnan Lu 1,  Mei Li 4,  Xin Wen 3 5,  Shenghua Gao 6,  Peng Zhan 6,  Lijun Rong 7,  Liqiang Feng 1,  Peng Gong 5,  Jun He 1,  Xinwen Chen 4 5,  Xiaoli Xiong 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 Graduate School of Guangzhou Medical University, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 3 Medical School, University of Chinese Academy of Sciences, Beijing 100864, China.
  • 4 Guangzhou National Laboratory, Guangzhou 510005, China.
  • 5 Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430061, China.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250013, China.
  • 7 Departments of Microbiology and Immunology, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
PMID: 39964914 DOI: 10.1093/procel/pwaf014
Abstract

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of Other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.

Keywords

Cryo-EM; L-P polymerase complex; Nipah virus; Paramyxovirus; RNA-dependent RNA polymerase (RdRp).

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