|3o9j, resolution 2.00Å ()|
Influenza NA in complex with compound 5
Influenza virus sialidase has an essential role in the virus' life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the '150-loop', providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.
Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase., Rudrawar S, Dyason JC, Rameix-Welti MA, Rose FJ, Kerry PS, Russell RJ, van der Werf S, Thomson RJ, Naffakh N, von Itzstein M, Nat Commun. 2010 Nov;1(8):113. Epub 2010 Nov 16. PMID:21081911
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Rudrawar S, Dyason JC, Rameix-Welti MA, Rose FJ, Kerry PS, Russell RJ, van der Werf S, Thomson RJ, Naffakh N, von Itzstein M. Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase. Nat Commun. 2010 Nov;1(8):113. Epub 2010 Nov 16. PMID:21081911 doi:10.1038/ncomms1114