Structural insights into the dynamic mechanism of bornavirus polymerase

• 成果类型: Article
• 署名作者: Yang, Ge; Wang, Dong; Liu, Bin
• 署名单位: University of Minnesota System
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10518
• DOI: 10.1073/pnas.2504779122
• 发表日期: 2025-09-30
• 关键词: l-protein; virus; alignment; complex; domain; ORGANIZATION; ribavirin; sequence; features; gdp

摘要

Borna disease virus 1 (BoDV-1), an emerging zoonotic pathogen from the Bornaviridae family, is neurotropic and can infect a variety of mammalian hosts, including humans. Linked to severe encephalitis and high mortality, BoDV-1 currently lacks licensed treatments or vaccines. The BoDV-1 polymerase complex, comprising the large (L) and phosphoprotein (P) subunits, is crucial for viral replication and transcription, making it a promising target for antiviral intervention. Here, we present the cryoelectron microscopy structure of the apo BoDV-1 L-P complex, revealing a unique mitten-shaped architecture. The structure characterizes key domains involved in RNA synthesis, including RNA-dependent RNA polymerase, polyribonucleotidyltransferase, and an inactive methyltransferase domain. While no RNA or NTPs were visible, we observed distinct conformational states, showing large-scale rearrangements of the P tetramer and L domains, as well as remodeling of the RNA template, nucleoside triphosphates, and nascent RNA entrances and/or exits, upon introducing RNA and NTPs. These findings highlight the dynamic structural changes probably associated with polymerase activity and advance the understanding of the BoDV-1 polymerase mechanisms, offering a basis for developing targeted antiviral strategies against this deadly pathogen.