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: Toshiharu Tsurumura, Hao Qiu, Toru Yoshida, Yayoi Tsumori, Dai Hatakeyama, Takashi Kuzuhara, Hideaki Tsuge
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e82020 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24312396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA Cap Analogs
• 7-methylguanosine triphosphate

Topics

• Amino Acid Sequence
• Crystallography, X-Ray
• Humans
• Influenza A Virus, H1N1 Subtype (chemistry)
• Molecular Conformation
• Molecular Sequence Data
• Mutation
• RNA Cap Analogs (chemistry, metabolism)
• Sequence Homology, Amino Acid