1L7H

Crystal structure of R292K mutant influenza virus neuraminidase in complex with BCX-1812

Summary for 1L7H

• Entry DOI: 10.2210/pdb1l7h/pdb
• Related: 1L7F 1L7G 2QWE 2QWH
• Descriptor: neuraminidase, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: n9 neuraminidase, hydrolase, influenza, glycosylated protein, bcx-1812, r292k mutant
• Biological source: Influenza A virus
• Cellular location: Virion membrane (By similarity): P03472
• Total number of polymer chains: 1
• Total formula weight: 46301.39

Authors

Smith, B.J.,McKimm-Breshkin, J.L.,McDonald, M.,Fernley, R.T.,Varghese, J.N.,Colman, P.M. (deposition date: 2002-03-15, release date: 2002-05-29, Last modification date: 2024-11-13)

Primary citation

Smith, B.J.,McKimm-Breshkin, J.L.,McDonald, M.,Fernley, R.T.,Varghese, J.N.,Colman, P.M.
Structural studies of the resistance of influenza virus neuramindase to inhibitors.
J.Med.Chem., 45:2207-2212, 2002

PubMed Abstract: Zanamivir 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.

PubMed: 12014958
DOI: 10.1021/jm010528u

Experimental method

X-RAY DIFFRACTION (1.85 Å)