title: The cap-binding site of influenza virus protein PB2 as a drug target.
abstract: The RNA polymerase of influenza virus consists of three subunits: PA, PB1 and PB2. It uses a unique `cap-snatching' mechanism for the transcription of viral mRNAs. The cap-binding domain of the PB2 subunit (PB2cap) in the viral polymerase binds the cap of a host pre-mRNA molecule, while the endonuclease of the PA subunit cleaves the RNA 10-13 nucleotides downstream from the cap. The capped RNA fragment is then used as the primer for viral mRNA transcription. The structure of PB2cap from influenza virus H1N1 A/California/07/2009 and of its complex with the cap analog m(7)GTP were solved at high resolution. Structural changes are observed in the cap-binding site of this new pandemic influenza virus strain, especially the hydrophobic interactions between the ligand and the target protein. m(7)GTP binds deeper in the pocket than some other virus strains, much deeper than the host cap-binding proteins. Analysis of the new H1N1 structures and comparisons with other structures provide new insights into the design of small-molecule inhibitors that will be effective against multiple strains of both type A and type B influenza viruses.
authors.affiliation: Department of Chemistry, Georgia State University, PO Box 3965, Atlanta, GA 30302, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Severin
authors.affiliation: Department of Chemistry, Georgia State University, PO Box 3965, Atlanta, GA 30302, USA.
authors.forename: Tales
authors.initials: T
authors.lastname: Rocha de Moura
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research and School of Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Georgia State University, PO Box 3965, Atlanta, GA 30302, USA.
authors.forename: Keqin
authors.initials: K
authors.lastname: Li
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research and School of Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Georgia State University, PO Box 3965, Atlanta, GA 30302, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Luo
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006160:Guanosine Triphosphate / Q000737:chemistry; D006860:Hydrogen Bonding; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology; D008958:Models, Molecular; D012314:RNA Cap Analogs / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; C502893:PB2 protein, influenza virus; D012314:RNA Cap Analogs; D014764:Viral Proteins; D006160:Guanosine Triphosphate
keywords: antiviral; broad spectrum; drug design; inhibitor