Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase

• DOI: 10.1371/journal.ppat.1002831
• Publication Date: 2012-08-02T21:28:41Z
• Authors: Eva Kowalinski; Chloe Zubieta; Andrea Wolkerstorfer; Oliver H. J. Szolar; Rob W. H. Ruigrok; Stephen Cusack
• Keywords: Transcription

It is generally recognised that novel antiviral drugs, less prone to resistance, would be a desirable alternative current drug options in order able treat potentially serious influenza infections. The viral polymerase, which performs transcription and replication of the RNA genome, an attractive target for drugs since potent polymerase inhibitors could directly stop at early stage. Recent structural studies on functional domains heterotrimeric comprises subunits PA, PB1 PB2, open way structure based approach optimise replication. In particular, unique cap-snatching mechanism can inhibited by targeting either PB2 cap-binding or PA endonuclease domains. Here we describe high resolution X-ray co-crystal structures 2009 pandemic H1N1 (pH1N1) domain with series specific inhibitors, including four diketo compounds green tea catechin, all chelate two critical manganese ions active site enzyme. Comparison binding mode different mononucleotide phosphate highlights, firstly, how substituent groups basic metal scaffold orientated bind distinct sub-pockets within cavity, secondly, plasticity certain elements result induced fit binding. These results will important optimising design more activity virus polymerase.