PDBsum entry 1b9t

Hydrolase

PDB id: 1b9t

Contents

Protein chain

390 a.a.

Ligands

NAG

RAI

Metals

_CA ×2

Waters ×112

PDB id:

1b9t

Name:

Hydrolase

Title:

Novel aromatic inhibitors of influenza virus neuraminidase make selective interactions with conserved residues and water molecules in the active site

Structure:

Protein (neuraminidase). Chain: a. Synonym: sialidase. Ec: 3.2.1.18

Source:

Influenza b virus (b/lee/40). Organism_taxid: 107412. Strain: b/lee/40

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.40Å R-factor: 0.195 R-free: 0.271

Authors:

J.B.Finley,V.R.Atigadda,F.Duarte,J.J.Zhao,W.J.Brouillette,G.M.Air, M.Luo

Key ref:

J.B.Finley et al. (1999). Novel aromatic inhibitors of influenza virus neuraminidase make selective interactions with conserved residues and water molecules in the active site. J Mol Biol, 293, 1107-1119. PubMed id: 10547289 DOI: 10.1006/jmbi.1999.3180

Date:

15-Feb-99 Release date: 27-Feb-99

Protein chain

P03474  (NRAM_INBLE) -  Neuraminidase from Influenza B virus (strain B/Lee/1940)

Seq: 466 a.a.

Struc: 390 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.2.1.18 - exo-alpha-sialidase.
• Reaction: Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)-glycosidic linkages of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates.

DOI no: 10.1006/jmbi.1999.3180

J Mol Biol 293:1107-1119 (1999)

PubMed id: 10547289

Novel aromatic inhibitors of influenza virus neuraminidase make selective interactions with conserved residues and water molecules in the active site.

J.B.Finley, V.R.Atigadda, F.Duarte, J.J.Zhao, W.J.Brouillette, G.M.Air, M.Luo.

ABSTRACT

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.

Selected figure(s)

Figure 3.
Figure 3. Comparison of the pyrrolidinone ring conformation and interactions of the hydroxymethyl groups with the NA active site. (a) BANA205, (b) BANA206. In (a), the pyrrolidinone ring is nearly flat, while in (b) the ring is puckered. The puckering difference allows the hydroxymethyl groups to interact differently with NA residues. Active site residues are indicated.

Figure 4.
Figure 4. Overlay of the com- plexes of BANA205 and BANA206 with B/Lee/40 NA, and native B/ Lee/40 NA showing water del- etions and movements, as well as the movement of the Glu275 side- chain. Blue is native B/Lee/40 NA, red is B/Lee/40 NA complexed with BANA206, and green is B/ Lee/40 NA complexed with BANA205. The pyrrolidinone ring and the two hydroxymethyl groups replace water molecules WAT677, WAT725 and WAT723. The induced rotation of Glu275 by the inhibitor molecules is shown. Movement of WAT724 is shown by the arrow and it is pushed ~1.4 Å deeper into the binding pocket. In the case of BANA206, WAT724 does not move because the rotation of Glu275 supplies WAT724 with a new hydrogen bond to compensate for the lost hydrogen bond from the missing WAT723 (Figure 5(b)).

The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 293, 1107-1119) copyright 1999.

Figures were selected by an automated process.