title: Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1.
abstract: Influenza A viruses cause the respiratory illness influenza, which can be mild to fatal depending on the strain and host immune response. The flu polymerase acidic (PA), polymerase basic 1 (PB1), and polymerase basic 2 (PB2) proteins comprise the RNA-dependent RNA polymerase complex responsible for viral genome replication. The first crystal structures of the C-terminal domain of PA (PA-CTD) in the absence of PB1-derived peptides show a number of structural changes relative to the previously reported PB1-peptide bound structures. The human A/WSN/1933 (H1N1) and avian A/Anhui1/2013 (H7N9) strain PA-CTD proteins exhibit the same global topology as other strains in the absence of PB1, but differ extensively in the PB1 binding pocket including a widening of the binding groove and the unfolding of a β-turn. Both PA-CTD proteins exhibited a significant increase in thermal stability in the presence of either a PB1-derived peptide or a previously reported inhibitor in differential scanning fluorimetry assays. These structural changes demonstrate plasticity in the PA-PB1 binding interface which may be exploited in the development of novel therapeutics.
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Spencer O
authors.initials: SO
authors.lastname: Moen
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Abendroth
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Fairman
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Ruth O
authors.initials: RO
authors.lastname: Baydo
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Jameson
authors.initials: J
authors.lastname: Bullen
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kirkwood
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Barnes
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Raymond
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Begley
authors.affiliation: Arisan Therapeutics, 11189 Sorrento Valley Rd, Suite 104, San Diego CA 92121, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Henkel
authors.affiliation: Arisan Therapeutics, 11189 Sorrento Valley Rd, Suite 104, San Diego CA 92121, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: McCormack
authors.affiliation: Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Tam
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Phan
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Staker
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Stacy
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA [3] University of Washington, Department of Medical Education and Biomedical Informatics &Department of Global Health, Seattle WA 98195, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Myler
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Lorimer
authors.affiliation: 1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Edwards
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004795:Enzyme Stability; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry* / Q000201:enzymology; D064766:Influenza A Virus, H7N9 Subtype / Q000737:chemistry* / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
chemical_list: C061290:PA protein, influenza viruses; D011994:Recombinant Proteins; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase
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