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Crystal structure of R292K mutant influenza virus neuraminidase in complex with BCX-1812Crystal structure of R292K mutant influenza virus neuraminidase in complex with BCX-1812
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedZanamivir and oseltamivir, specific inhibitors of influenza virus neuraminidase, have significantly different characteristics in resistance studies. In both cases resistance is known to arise through mutations in either the hemagglutinin or neuraminidase surface proteins. A new inhibitor under development by Biocryst Pharmaceuticals, BCX-1812, has both a guanidino group, as in zanamivir, and a bulky hydrophobic group, as in oseltamivir. Using influenza A/NWS/Tern/Australia/G70C/75 (H1N9), neuraminidase variants E119G and R292K have previously been selected by different inhibitors. The sensitivity of these variants to BCX-1812 has now been measured and found in both cases to be intermediate between those of zanamivir and oseltamivir. In addition, the X-ray crystal structures of the complexes of BCX-1812 with the wild type and the two mutant neuraminidases were determined. The ligand is bound in an identical manner in each structure, with a rearrangement of the side chain of E276 from its ligand-free position. A structural explanation of the mechanism of resistance of BCX-1812, relative to zanamivir and oseltamivir in particular, is provided. Structural studies of the resistance of influenza virus neuramindase to inhibitors.,Smith BJ, McKimm-Breshkin JL, McDonald M, Fernley RT, Varghese JN, Colman PM J Med Chem. 2002 May 23;45(11):2207-12. PMID:12014958[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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