title: Conformational polymorphism of m7GTP in crystal structure of the PB2 middle domain from human influenza A virus.
abstract: Influenza pandemics with human-to-human transmission of the virus are of great public concern. It is now recognized that a number of factors are necessary for human transmission and virulence, including several key mutations within the PB2 subunit of RNA-dependent RNA polymerase. The structure of the middle domain in PB2 has been revealed with or without m(7)GTP, thus the middle domain is considered to be novel target for structure-based drug design. Here we report the crystal structure of the middle domain of H1N1 PB2 with or without m(7)GTP at 1.9 Å and 2.0 Å resolution, respectively, which has two mutations (P453H, I471T) to increase electrostatic potential and solubility. Here we report the m(7)GTP has unique conformation differ from the reported structure. 7-methyl-guanine is fixed in the pocket, but particularly significant change is seen in ribose and triphosphate region: the buried 7-methyl-guanine indeed binds in the pocket forming by H357, F404, E361 and K376 but the triphosphate continues directly to the outer domain. The presented conformation of m(7)GTP may be a clue for the anti-influenza drug-design.
authors: Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kyoto, Japan.
authors: Toshiharu
authors: T
authors: Tsurumura
authors: Hao
authors: H
authors: Qiu
authors: Toru
authors: T
authors: Yoshida
authors: Yayoi
authors: Y
authors: Tsumori
authors: Dai
authors: D
authors: Hatakeyama
authors: Takashi
authors: T
authors: Kuzuhara
authors: Hideaki
authors: H
authors: Tsuge
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D012314:RNA Cap Analogs / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D012314:RNA Cap Analogs; C017516:7-methylguanosine triphosphate