Conformational polymorphism of m7GTP in crystal structure of the PB2 middle domain from human influenza A virus

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 th...

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Bibliographic Details
Published in:PloS one 2013-11, Vol.8 (11), p.e82020-e82020
Main Authors: Tsurumura, Toshiharu, Qiu, Hao, Yoshida, Toru, Tsumori, Yayoi, Hatakeyama, Dai, Kuzuhara, Takashi, Tsuge, Hideaki
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Avian flu
Binding sites
Conformation
Crystal structure
Crystallography, X-Ray
DNA-directed RNA polymerase
Drug development
Electrostatic properties
Genomes
Guanine
Humans
Influenza
Influenza A
Influenza A Virus, H1N1 Subtype - chemistry
Life sciences
Molecular Conformation
Molecular Sequence Data
Mutation
Pandemics
Pharmaceutical sciences
Polymorphism
Proteins
Public concern
Ribonucleic acid
Ribose
RNA
RNA Cap Analogs - chemistry
RNA Cap Analogs - metabolism
RNA-directed RNA polymerase
Sequence Homology, Amino Acid
Solubility
Swine flu
Virulence
Viruses
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0082020