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

  • Protein Cell. 2025 Feb 18:pwaf014. doi: 10.1093/procel/pwaf014.
Lu Xue  1 ,  Tiancai Chang  1  2 ,  Jiacheng Gui  1  3 ,  Zimu Li  1  4 ,  Heyu Zhao  1  3 ,  Bingqian Zou  1  2 ,  Junnan Lu  1 ,  Mei Li  4 ,  Xin Wen  3 ,  Shenghua Gao  5 ,  Peng Zhan  5 ,  Lijun Rong  6 ,  Liqiang Feng  1 ,  Peng Gong  7 ,  Jun He  1 ,  Xinwen Chen  4  7 ,  Xiaoli Xiong  1
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. Guangzhou Medical University, Guangzhou 511436, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100864, China.
  • 4. Guangzhou National Laboratory, Guangzhou 510005, China.
  • 5. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250013, China.
  • 6. Department of Microbiology and Immunology, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 7. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430061, China.
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. 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.

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