The Crystal Structure of the PB2 Cap-binding Domain of Influenza B Virus Reveals a Novel Cap Recognition Mechanism [Protein Structure and Folding]

February 17th, 2015 by Liu, Y., Yang, Y., Fan, J., He, R., Luo, M., Zheng, X.

The influenza RNA-dependent RNA polymerase is a core enzyme required for both transcription and replication of the virus RNA genome, which makes it a potential drug target for the influenza virus. To detect the feature of cap-dependent transcription of influenza B virus (FluB) polymerase, we determined the crystal structures of the wild-type FluB polymerase PB2 subunit cap-binding domain (PB2cap) with bound GDP, and the mutant FluB Q325F PB2cap with bound m7GDP or GDP. These structures revealed that, distinct from influenza A virus (FluA) PB2cap, the guanine and ribose moieties of substrates invert in FluB PB2caps. Moreover, we characterized the substrate specificity and affinity of the PB2caps using isothermal titration calorimetry. FluB PB2cap has a weaker affinity for m7GDP than FluA PB2cap. Unlike FluA PB2cap that has a preference for m7GDP in comparison to GDP, FluB PB2cap shows an analogous affinity for both substrates. Replacement of FluB PB2 Glu325 by Phe, the corresponding residue of FluA PB2, could increase the binding affinity of FluB PB2cap for m7GDP to an approximate level of FluA PB2cap, and cause a significant higher affinity to GDP. This study indicated that FluB PB2cap has a unique cap-recognition mechanism compared to FluA PB2cap, which provides molecular insight into inhibitor design targeting FluB PB2cap.
  • Posted in Journal of Biological Chemistry, Publications
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