1BJI

THE X-RAY STRUCTURE OF A COMPLEX OF TERN N9 INFLUENZA VIRUS NEURAMINIDASE COMPLEXED WITH THE GLAXO 6-CARBOXAMIDE SIALIC ACID ANALOGUE GR217029

Summary for 1BJI

• Entry DOI: 10.2210/pdb1bji/pdb
• Descriptor: NEURAMINIDASE, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose, ... (7 entities in total)
• Functional Keywords: neuraminidase, influenza protein, inhibitor complex, 6-carboxamide derivative, sialic acid analogue, glaxo gr217029, hydrolase, glycoprotein
• Biological source: Influenza A virus
• Cellular location: Virion membrane (By similarity): P03472
• Total number of polymer chains: 1
• Total formula weight: 45848.83

Authors

Varghese, J.N. (deposition date: 1997-12-03, release date: 1998-06-03, Last modification date: 2024-10-23)

Primary citation

Taylor, N.R.,Cleasby, A.,Singh, O.,Skarzynski, T.,Wonacott, A.J.,Smith, P.W.,Sollis, S.L.,Howes, P.D.,Cherry, P.C.,Bethell, R.,Colman, P.,Varghese, J.
Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B.
J.Med.Chem., 41:798-807, 1998

PubMed Abstract: The first paper in this series (see previous article) described structure-activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein-ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In sialidase from type A virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, whereas in type B enzyme, significant distortion of the protein is observed. The results suggest that the decreased affinity in enzyme from influenza B is directly correlated with the small changes that occur in the amino acid residue interactions accompanying ligand binding. Molecular dynamics calculations have shown that the tendency for salt-bridge formation is greater in influenza A sialidase than influenza B sialidase and that this tendency is a useful descriptor for the prediction of inhibitor potency.

PubMed: 9526556
DOI: 10.1021/jm9703754

Experimental method

X-RAY DIFFRACTION (2 Å)