title: The structural basis for an essential subunit interaction in influenza virus RNA polymerase.
abstract: Influenza A virus is a major human and animal pathogen with the potential to cause catastrophic loss of life. The virus reproduces rapidly, mutates frequently and occasionally crosses species barriers. The recent emergence in Asia of avian influenza related to highly pathogenic forms of the human virus has highlighted the urgent need for new effective treatments. Here we demonstrate the importance to viral replication of a subunit interface in the viral RNA polymerase, thereby providing a new set of potential drug binding sites entirely independent of surface antigen type. No current medication targets this heterotrimeric polymerase complex. All three subunits, PB1, PB2 and PA, are required for both transcription and replication. PB1 carries the polymerase active site, PB2 includes the capped-RNA recognition domain, and PA is involved in assembly of the functional complex, but so far very little structural information has been reported for any of them. We describe the crystal structure of a large fragment of one subunit (PA) of influenza A RNA polymerase bound to a fragment of another subunit (PB1). The carboxy-terminal domain of PA forms a novel fold, and forms a deep, highly hydrophobic groove into which the amino-terminal residues of PB1 can fit by forming a 3(10) helix.
authors.affiliation: Protein Design Laboratory, Yokohama City University, 1-7-29 Suehiro, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Obayashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kawai
authors.forename: Naoya
authors.initials: N
authors.lastname: Shibayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawaguchi
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Nagata
authors.forename: Jeremy R H
authors.initials: JR
authors.lastname: Tame
authors.forename: Sam-Yong
authors.initials: SY
authors.lastname: Park
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C061290:PA protein, influenza viruses; C057027:PB2 protein, Influenzavirus A; D021122:Protein Subunits; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase