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

Lu XUE; Tiancai CHANG; Jiacheng GUI; Zimu LI; Heyu ZHAO; Binqian ZOU; Junnan LU; Mei LI; Xin WEN; Shenghua GAO; Peng ZHAN; Lijun RONG; Liqiang FENG; Peng GONG; Jun HE; Xinwen CHEN; Xiaoli XIONG

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

Author: Lu XUE ¹ ; Tiancai CHANG ¹ ; Jiacheng GUI ¹ ; Zimu LI ¹ ; Heyu ZHAO ¹ ; Binqian ZOU ¹ ; Junnan LU ¹ ; Mei LI ² ; Xin WEN ³ ; Shenghua GAO ⁴ ; Peng ZHAN ⁴ ; Lijun RONG ⁵ ; Liqiang FENG ¹ ; Peng GONG ⁶ ; Jun HE ¹ ; Xinwen CHEN ² ; Xiaoli XIONG ¹
Author Information

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 National Laboratory, Guangzhou 510005, China.
3. Medical School, University of Chinese Academy of Sciences, Beijing 100864, China.
4. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250013, China.
5. Departments of Microbiology and Immunology, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
6. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430061, China.
Publication Type:Journal Article
Keywords: Cryo-EM; L-P polymerase complex; Nipah virus; Paramyxovirus; RNA-dependent RNA polymerase (RdRp)
MeSH: Nipah Virus/chemistry*; Cryoelectron Microscopy; Viral Proteins/genetics*; RNA-Dependent RNA Polymerase/genetics*; Phosphoproteins/genetics*; Humans; Models, Molecular; Protein Binding
From: Protein & Cell 2025;16(8):705-723
CountryChina
Language:English
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.