Secondary Objectives

The secondary objective of FLUPHARM is enhancing further our fundamental understanding of the structure and cellular function of the influenza polymerase.

The major goals of this part of the project are:

  • To elucidate the detailed three-dimensional structure of the entire polymerase complex using a combination of cryo-electron microscopy and X-ray crystallography. Ideally, we want to have a crystal structure of the trimeric complex. Prior to this, it is likely we will need to develop a quasi-atomic model by fitting high-resolution structures of polymerase fragments into a cryo-electron microscopy map. In addition to this, the atomic resolution of the third polymerase active site, the nucleotidyl-transfer site on the PB1 subunit-, may provide new targets for future drug-design.
  • To enhance the understanding of the polymerase function in a cellular context, and its mutational adaptation during inter-species transmission. We aim to develop a comprehensive model of polymerase trafficking and assembly in infected cells, using fluorescent labelling and live cell imaging of polymerase, RNPs (ribonucleoproteins) and virus.The mechanistic model of polymerase function will be improved through a combination of structural and functional studies. In addition, the role of host factors interacting with the polymerase both in uninfected cells and in the pathogenicity of viral infection will be characterized using animal models.

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