Structural and functional analysis of the Nipah virus polymerase complex

被引：8

作者：

Hu, Side ^{[1
]}

Kim, Heesu ^{[2
]}

Yang, Pan ^{[1
]}

Yu, Zishuo

Ludeke, Barbara ^{[2
]}

Mobilia, Shawna ^{[2
]}

Pan, Junhua ^{[3
,4
]}

Stratton, Margaret ^{[5
]}

Bian, Yuemin ^{[6
]}

Fearns, Rachel ^{[2
]}

Abraham, Jonathan ^{[1
,7
,8
,9
]}

机构：

[1] Blavatnik Inst, Harvard Med Sch, Dept Microbiol, Boston, MA 02115 USA

[2] Boston Univ, Chobanian & Avedisian Sch Med, Dept Virol Immunol & Microbiol, Boston, MA 02215 USA

[3] Hubei Univ Technol, Biomed Res Inst, Wuhan, Peoples R China

[4] Hubei Univ Technol, Sch Life & Hlth Sci, Wuhan, Peoples R China

[5] Univ Massachusetts, Dept Biochem & Mol Biol, Amherst, MA 01002 USA

[6] Shanghai Univ, Sch Med, Shanghai, Peoples R China

[7] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA

[8] Broad Inst MIT & Harvard, Ctr Integrated Solut Infect Dis, Cambridge, MA 02142 USA

[9] Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

CELL | 2025年 / 188卷 / 03期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

VESICULAR STOMATITIS-VIRUS; DEPENDENT RNA-POLYMERASE; L PROTEIN; PHOSPHOPROTEIN; VISUALIZATION; REPLICATION; PREDICTION; FEATURES; CULTURE; SYSTEM;

D O I：

10.1016/j.cell.2024.12.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of alpha-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.

引用

页码：688 / 703.e18

页数：35

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