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PDBsum entry 1b9s

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protein ligands metals links
Hydrolase PDB id
1b9s
Jmol
Contents
Protein chain
390 a.a.
Ligands
NAG
FDI
Metals
_CA ×2
Waters ×120
PDB id:
1b9s
Name: Hydrolase
Title: Novel aromatic inhibitors of influenza virus neuraminidase m selective interactions with conserved residues and water mo 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. Cellular_location: cell membrane
Resolution:
2.50Å     R-factor:   0.174     R-free:   0.251
Authors: J.B.Finley,V.R.Atigadda,F.Duarte,J.J.Zhao,W.J.Brouillette,G. 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:   26-Feb-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03474  (NRAM_INBLE) -  Neuraminidase
Seq:
Struc:
466 a.a.
390 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.2.1.18  - Exo-alpha-sialidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   3 terms 
  Biological process     carbohydrate metabolic process   1 term 
  Biochemical function     exo-alpha-sialidase activity     1 term  

 

 
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21469159 S.Y.Lu, Y.J.Jiang, J.Lv, J.W.Zou, and T.X.Wu (2011).
Role of bridging water molecules in GSK3β-inhibitor complexes: insights from QM/MM, MD, and molecular docking studies.
  J Comput Chem, 32, 1907-1918.  
19390154 P.M.Dominiak, A.Volkov, A.P.Dominiak, K.N.Jarzembska, and P.Coppens (2009).
Combining crystallographic information and an aspherical-atom data bank in the evaluation of the electrostatic interaction energy in an enzyme-substrate complex: influenza neuraminidase inhibition.
  Acta Crystallogr D Biol Crystallogr, 65, 485-499.  
16374623 A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.
  J Mol Model, 12, 422-431.  
17103017 M.Zheng, K.Yu, H.Liu, X.Luo, K.Chen, W.Zhu, and H.Jiang (2006).
QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR.
  J Comput Aided Mol Des, 20, 549-566.  
15159560 B.S.Lommer, S.M.Ali, S.N.Bajpai, W.J.Brouillette, G.M.Air, and M.Luo (2004).
A benzoic acid inhibitor induces a novel conformational change in the active site of Influenza B virus neuraminidase.
  Acta Crystallogr D Biol Crystallogr, 60, 1017-1023.
PDB codes: 1uja 1vcj
14696043 M.A.Wouters, K.K.Lau, and P.J.Hogg (2004).
Cross-strand disulphides in cell entry proteins: poised to act.
  Bioessays, 26, 73-79.  
12756610 A.T.García-Sosa, R.L.Mancera, and P.M.Dean (2003).
WaterScore: a novel method for distinguishing between bound and displaceable water molecules in the crystal structure of the binding site of protein-ligand complexes.
  J Mol Model, 9, 172-182.  
  12488615 N.Shahrour (2001).
The Role of Neuraminidase Inhibitors in the Treatment and Prevention of Influenza.
  J Biomed Biotechnol, 1, 89-90.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.