Download Structural insights into RNA synthesis by the influenza virus

Structural insights into RNA synthesis by the influenza virus
transcription-replication machine.
Dr. Stephen Cusack FRS
European Molecular Biology Laboratory, Grenoble, France
Short abstract: The ‘flu is caused by the highly infectious, rapidly evolving and potentially
dangerous influenza virus. We study the viral replication machine, its RNA-dependent RNA
polymerase. This is of fundamental interest but will also help understand avian to human
interspecies transmission of the virus and promote development of new anti-influenza drugs.
Influenza, which is a member of the Orthomyxoviridae family of segmented negative strand
RNA viruses (sNSV), continues to have an enormous impact on world-wide public health. The eight
genome segments are individually packaged by the viral nucleoprotein into ribonucleoprotein
particles (RNPs), which are the functional replication units. Transcription, generating capped and
polyadenylated viral mRNAs, and replication, generating full-length genome or antigenome copies
(vRNA and cRNA respectively), are performed by the same virally encoded RNA-dependent RNA
polymerase, the viral replication machine. In general, sNSV polymerases have two unique features.
Firstly, they perform transcription by the ‘cap-snatching’ mechanism, whereby short 5′ capped RNA
fragments are cleaved from host cell mRNA by an endonuclease intrinsic to the polymerase and then
used to prime synthesis of viral mRNAs. Secondly, they recognise each genome segment via their
highly conserved, quasi-complementary 3′ and 5′ extremities, known as the promoter. Several recent
crystal structures of promoter bound influenza A and B polymerase that shed light on multiple aspects
of polymerase function will be discussed and their implication for novel anti-viral drug design
targeting directly viral replication highlighted.
References
1. Structure of influenza A polymerase bound to the viral RNA promoter. Pflug A, Guilligay D, Reich S,
Cusack S. Nature. 2014;516 (7531):355-60.
2. Structural insight into cap-snatching and RNA synthesis by influenza polymerase. Reich S, Guilligay D,
Pflug A, Malet H, Berger I, Crépin T, Hart D, Lunardi T, Nanao M, Ruigrok RW, Cusack S. Nature. 2014;516
(7531):361-6.
3. Structural insights into bunyavirus replication and its regulation by the vRNA promoter. Gerlach, P.,
Malet, H., Cusack, S. and Reguera, J. Cell. 2015;161(6):1267-79.
4. Influenza polymerase can adopt an alternative configuration involving a radical repacking of PB2
domains. Thierry E, Guilligay D, et al. Mol Cell. 2016.
5. Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of
influenza pH1N1 (2009) polymerase. Kowalinski, E., Zubieta, C., Wolkerstorfer, A., Szolar, O.H.J., Ruigrok,
R.W.H. and Cusack, S. PLoS Pathog. 2012;8(8):e1002831.