1b9t

NOVEL AROMATIC INHIBITORS OF INFLUENZA VIRUS NEURAMINIDASE MAKE SELECTIVE INTERACTIONS WITH CONSERVED RESIDUES AND WATER MOLECULES IN THE ACTIVE SITE

spinqualitylabelsall models 1b9t, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1b9t is a 1 chain structure with sequence from Influenza b virus (b/lee/40). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, NAG, RAI Activity: Exo-alpha-sialidase, with EC number 3.2.1.18 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NRAM_INBLE] Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus release. Additionally helps virus spread through the circulation by further removing sialic acids from the cell surface. These cleavages prevent self-aggregation and ensure the efficient spread of the progeny virus from cell to cell. Otherwise, infection would be limited to one round of replication. Described as a receptor-destroying enzyme because it cleaves a terminal sialic acid from the cellular receptors. May facilitate viral invasion of the upper airways by cleaving the sialic acid moities on the mucin of the airway epithelial cells (By similarity). Publication Abstract from PubMed The active site of type A or B influenza virus neuraminidase is composed of 11 conserved residues that directly interact with the substrate, sialic acid. An aromatic benzene ring has been used to replace the pyranose of sialic acid in our design of novel neuraminidase inhibitors. A bis(hydroxymethyl)pyrrolidinone ring was constructed in place of the N-acetyl group on the sialic acid. The hydroxymethyl groups replace two active site water molecules, which resulted in the high affinity of the nanomolar inhibitors. However, these inhibitors have greater potency for type A influenza virus than for type B influenza virus. To resolve the differences, we determined the X-ray crystal structure of three benzoic acid substituted inhibitors bound to the active site of B/Lee/40 neuraminidase. The investigation of a hydrophobic aliphatic group and a hydrophilic guanidino group on the aromatic inhibitors shows changes in the interaction with the active site residue Glu275. The results provide an explanation for the difference in efficacy of these inhibitors against types A and B viruses, even though the 11 active site residues of the neuraminidase are conserved. Novel aromatic inhibitors of influenza virus neuraminidase make selective interactions with conserved residues and water molecules in the active site.,Finley JB, Atigadda VR, Duarte F, Zhao JJ, Brouillette WJ, Air GM, Luo M J Mol Biol. 1999 Nov 12;293(5):1107-19. PMID:10547289 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Neuraminidase

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