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Sci Rep. 2014 Aug 4;4:5944. doi: 10.1038/srep05944.

Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1.

Author information

1
1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
2
Arisan Therapeutics, 11189 Sorrento Valley Rd, Suite 104, San Diego CA 92121, USA.
3
Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA.
4
1] Seattle Structural Genomics Center for Infectious Disease (SSGCID) [2] Seattle BioMed, 307 Westlake Avenue North, Seattle WA 98109, USA.
5
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.

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.

PMID:
25089892
PMCID:
PMC4123200
DOI:
10.1038/srep05944
[Indexed for MEDLINE]
Free PMC Article

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