Article abstract
Nature Structural & Molecular Biology 15, 500 - 506 (2008)
Published online: 4 May 2008 | doi:10.1038/nsmb.1421
The structural basis for cap binding by influenza virus polymerase subunit PB2
Delphine Guilligay1,2,5, Franck Tarendeau1,2,5, Patricia Resa-Infante3, Rocío Coloma3, Thibaut Crepin1,2, Peter Sehr4, Joe Lewis4, Rob W H Ruigrok2, Juan Ortin3, Darren J Hart1,2 & Stephen Cusack1,2
Abstract
Influenza virus mRNAs are synthesized by the trimeric viral polymerase using short capped primers obtained by a 'cap-snatching' mechanism. The polymerase PB2 subunit binds the 5' cap of host pre-mRNAs, which are cleaved after 10–13 nucleotides by the PB1 subunit. Using a library-screening method, we identified an independently folded domain of PB2 that has specific cap binding activity. The X-ray structure of the domain with bound cap analog m7GTP at 2.3-Å resolution reveals a previously unknown fold and a mode of ligand binding that is similar to, but distinct from, other cap binding proteins. Binding and functional studies with point mutants confirm that the identified site is essential for cap binding in vitro and cap-dependent transcription in vivo by the trimeric polymerase complex. These findings clarify the nature of the cap binding site in PB2 and will allow efficient structure-based design of new anti-influenza compounds inhibiting viral transcription.
- Grenoble Outstation, European Molecular Biology Laboratory, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France.
- Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMR 5233, 6 rue Jules Horowitz, 38042 Grenoble Cedex 9, France.
- Centro Nacional de Biotecnología (CSIC), Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain, and CIBER de Enfermedades Respiratorias.
- Chemical Biology Core Facility, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
- These authors contributed equally to this work.
Correspondence to: Stephen Cusack1,2 e-mail: cusack@embl.fr
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