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

共 72 条

[1] Structure of a paramyxovirus polymerase complex reveals a unique methyltransferase-CTD conformation [J].

Abdella, Ryan ;

Aggarwal, Megha ;

Okura, Takashi ;

Lamb, Robert A. ;

He, Yuan .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2020, 117 (09) :4931-4941

[2] Accurate structure prediction of biomolecular interactions with AlphaFold 3 [J].

Abramson, Josh ;

Adler, Jonas ;

Dunger, Jack ;

Evans, Richard ;

Green, Tim ;

Pritzel, Alexander ;

Ronneberger, Olaf ;

Willmore, Lindsay ;

Ballard, Andrew J. ;

Bambrick, Joshua ;

Bodenstein, Sebastian W. ;

Evans, David A. ;

Hung, Chia-Chun ;

O'Neill, Michael ;

Reiman, David ;

Tunyasuvunakool, Kathryn ;

Wu, Zachary ;

Zemgulyte, Akvile ;

Arvaniti, Eirini ;

Beattie, Charles ;

Bertolli, Ottavia ;

Bridgland, Alex ;

Cherepanov, Alexey ;

Congreve, Miles ;

Cowen-Rivers, Alexander I. ;

Cowie, Andrew ;

Figurnov, Michael ;

Fuchs, Fabian B. ;

Gladman, Hannah ;

Jain, Rishub ;

Khan, Yousuf A. ;

Low, Caroline M. R. ;

Perlin, Kuba ;

Potapenko, Anna ;

Savy, Pascal ;

Singh, Sukhdeep ;

Stecula, Adrian ;

Thillaisundaram, Ashok ;

Tong, Catherine ;

Yakneen, Sergei ;

Zhong, Ellen D. ;

Zielinski, Michal ;

Zidek, Augustin ;

Bapst, Victor ;

Kohli, Pushmeet ;

Jaderberg, Max ;

Hassabis, Demis ;

Jumper, John M. .

NATURE, 2024, 630 (8016) :493-500

[3] The Phenix software for automated determination of macromolecular structures [J].

Adams, Paul D. ;

Afonine, Pavel V. ;

Bunkoczi, Gabor ;

Chen, Vincent B. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Hung, Li-Wei ;

Jain, Swati ;

Kapral, Gary J. ;

Kunstleve, Ralf W. Grosse ;

McCoy, Airlie J. ;

Moriarty, Nigel W. ;

Oeffner, Robert D. ;

Read, Randy J. ;

Richardson, David C. ;

Richardson, Jane S. ;

Terwilliger, Thomas C. ;

Zwart, Peter H. .

METHODS, 2011, 55 (01) :94-106

[4] Taxonomy of the order Mononegavirales: update 2019 [J].

Amarasinghe, Gaya K. ;

Ayllon, Maria A. ;

Bao, Yiming ;

Basler, Christopher F. ;

Bavari, Sina ;

Blasdell, Kim R. ;

Briese, Thomas ;

Brown, Paul A. ;

Bukreyev, Alexander ;

Balkema-Buschmann, Anne ;

Buchholz, Ursula J. ;

Chabi-Jesus, Camila ;

Chandran, Kartik ;

Chiapponi, Chiara ;

Crozier, Ian ;

de Swart, Rik L. ;

Dietzgen, Ralf G. ;

Dolnik, Olga ;

Drexler, Jan F. ;

Duerrwald, Ralf ;

Dundon, William G. ;

Duprex, W. Paul ;

Dye, John M. ;

Easton, Andrew J. ;

Fooks, Anthony R. ;

Formenty, Pierre B. H. ;

Fouchier, Ron A. M. ;

Freitas-Astua, Juliana ;

Griffiths, Anthony ;

Hewson, Roger ;

Horie, Masayuki ;

Hyndman, Timothy H. ;

Jiang, Daohong ;

Kitajima, Elliott W. ;

Kobinger, Gary P. ;

Kondo, Hideki ;

Kurath, Gael ;

Kuzmin, Ivan V. ;

Lamb, Robert A. ;

Lavazza, Antonio ;

Lee, Benhur ;

Lelli, Davide ;

Leroy, Eric M. ;

Li, Jianrong ;

Maes, Piet ;

Marzano, Shin-Yi L. ;

Moreno, Ana ;

Muhlberger, Elke ;

Netesov, Sergey V. ;

Nowotny, Norbert .

ARCHIVES OF VIROLOGY, 2019, 164 (07) :1967-1980

[5] Outbreak Investigation of Nipah Virus Disease in Kerala, India, 2018 [J].

Arunkumar, Govindakarnavar ;

Chandni, Radhakrishnan ;

Mourya, Devendra T. ;

Singh, Sujeet K. ;

Sadanandan, Rajeev ;

Sudan, Preeti ;

Bhargava, Balram ;

Gangakhedkar, Raman R. ;

Gupta, Nivedita ;

Bhargava, Balram ;

Mourya, D. T. ;

Yadav, Pragya D. ;

Shete, Anita M. ;

Sahay, Reema ;

Sudeep, A. ;

Bharadwaj, Sumit ;

Sugunan, A. P. ;

Manickam, P. ;

Bhatnagar, Tarun ;

Murhekar, Manoj ;

Arunkumar, Govindakarnavar ;

Abdulmajeed, Jazeel ;

Aswathyraj, Sushama ;

Santhosha, Devadiga ;

Anup, Jayaram ;

Sudheesh, Nittur ;

Anitha, Jagdesh ;

Robin, S. ;

Sabeena, Sasidharanpillai ;

Shakir, Muhammed ;

Sarthak, Pattanaik ;

Suresh, Prabhu ;

Maity, Hindol ;

Sheik, Shahin ;

Shilpa, C. ;

Karunakaran, Kavitha ;

Anjali, Aithal ;

Kumar, Sanjeeva ;

Venkatesh, Srinivasan ;

Ravindran, P. ;

Singh, Sujeet Kumar ;

Gupta, Naveen ;

Kulkarni, Sanket ;

Raghu, K. ;

Ali, M. K. Showkath ;

Jain, Ruchi ;

Chandra, Ramesh ;

Kiran, Jai ;

Khasnobis, Pradeep ;

Jain, S. K. .

JOURNAL OF INFECTIOUS DISEASES, 2019, 219 (12) :1867-1878

[6] Biochemical and structural studies of the oligomerization domain of the Nipah virus phosphoprotein: Evidence for an elongated coiled-coil homotrimer [J].

Blocquel, David ;

Beltrandi, Matilde ;

Erales, Jenny ;

Barbier, Pascale ;

Longhi, Sonia .

VIROLOGY, 2013, 446 (1-2) :162-172

[7] Structural Dynamics of the C-terminal X Domain of Nipah and Hendra Viruses Controls the Attachment to the C-terminal Tail of the Nucleocapsid Protein [J].

Bourhis, Jean-Marie ;

Yabukarski, Filip ;

Communie, Guillaume ;

Schneider, Robert ;

Volchkova, Valentina A. ;

Freneat, Mickael ;

Gerard, Francine C. ;

Ducournau, Corinne ;

Mas, Caroline ;

Tarbouriech, Nicolas ;

Jensen, Malene Ringkjobing ;

Volchkov, Viktor E. ;

Blackledge, Martin ;

Jamin, Marc .

JOURNAL OF MOLECULAR BIOLOGY, 2022, 434 (10)

[8]

Bowers K. J., 2006, P 2006 ACM IEEE C SU, DOI [DOI 10.1109/SC.2006.54, 10.1145/1188455.1188544]

[9] RNA elongation by respiratory syncytial virus polymerase is calibrated by conserved region V [J].

Braun, Molly R. ;

Deflube, Laure R. ;

Noton, Sarah L. ;

Mawhorter, Michael E. ;

Tremaglio, Chadene Z. ;

Fearns, Rachel .

PLOS PATHOGENS, 2017, 13 (12)

[10] Crystal Structure of the Nipah Virus Phosphoprotein Tetramerization Domain [J].

Bruhn, Jessica F. ;

Barnett, Katherine C. ;

Bibby, Jaclyn ;

Thomas, Jens M. H. ;

Keegan, Ronan M. ;

Rigden, Daniel J. ;

Bornholdt, Zachary A. ;

Saphire, Erica Ollmann .

JOURNAL OF VIROLOGY, 2014, 88 (01) :758-762

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