7EV8

Structure of Human Parainfluenza Virus 3 Unassembled Nucleoprotein in Complex with its viral chaperone

Summary for 7EV8

• Entry DOI: 10.2210/pdb7ev8/pdb
• Descriptor: Nucleoprotein, Phosphoprotein (3 entities in total)
• Functional Keywords: complex, inhibitor, hpiv3, nucleoprotein, viral protein
• Biological source: Human parainfluenza 3 virus (strain Wash/47885/57) (HPIV-3, Human parainfluenza 3 virus (strain NIH 47885)); More
• Total number of polymer chains: 2
• Total formula weight: 43710.74

Authors

Dong, X.F.,Chen, Z. (deposition date: 2021-05-20, release date: 2021-11-10, Last modification date: 2023-11-29)

Primary citation

Dong, X.,Wang, X.,Xie, M.,Wu, W.,Chen, Z.
Structural Basis of Human Parainfluenza Virus 3 Unassembled Nucleoprotein in Complex with Its Viral Chaperone.
J.Virol., 96:e0164821-e0164821, 2022

PubMed Abstract: Human parainfluenza virus 3 (HPIV3) belongs to the Paramyxoviridae, causing annual worldwide epidemics of respiratory diseases, especially in newborns and infants. The core components consist of just three viral proteins: nucleoprotein (N), phosphoprotein (P), and RNA polymerase (L), playing essential roles in replication and transcription of HPIV3 as well as other paramyxoviruses. Viral genome encapsidated by N is as a template and recognized by RNA-dependent RNA polymerase complex composed of L and P. The offspring RNA also needs to assemble with N to form nucleocapsids. The N is one of the most abundant viral proteins in infected cells and chaperoned in the RNA-free form (N) by P before encapsidation. In this study, we presented the structure of unassembled HPIV3 N in complex with the N-terminal portion of the P, revealing the molecular details of the N and the conserved N-P interaction. Combined with biological experiments, we showed that the P binds to the C-terminal domain of N mainly by hydrophobic interaction and maintains the unassembled conformation of N by interfering with the formation of N-RNA oligomers, which might be a target for drug development. Based on the complex structure, we developed a method to obtain the monomeric N. Furthermore, we designed a P-derived fusion peptide with 10-fold higher affinity, which hijacked the N and interfered with the binding of the N to RNA significantly. Finally, we proposed a model of conformational transition of N from the unassembled state to the assembled state, which helped to further understand viral replication. Human parainfluenza virus 3 (HPIV3) causes annual epidemics of respiratory diseases, especially in newborns and infants. For the replication of HPIV3 and other paramyxoviruses, only three viral proteins are required: phosphoprotein (P), RNA polymerase (L), and nucleoprotein (N). Here, we report the crystal structure of the complex of N and its chaperone P. We describe in detail how P acts as a chaperone to maintain the unassembled conformation of N. Our analysis indicated that the interaction between P and N is conserved and mediated by hydrophobicity, which can be used as a target for drug development. We obtained a high-affinity P-derived peptide inhibitor, specifically targeted N, and greatly interfered with the binding of the N to RNA, thereby inhibiting viral encapsidation and replication. In summary, our results provide new insights into the paramyxovirus genome replication and nucleocapsid assembly and lay the basis for drug development.

PubMed: 34730394
DOI: 10.1128/JVI.01648-21

Experimental method

X-RAY DIFFRACTION (3.234 Å)