PDBsum entry 1ivg

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Hydrolase (o-glycosyl) PDB id
Protein chains
388 a.a. *
_CA ×2
Waters ×375
* Residue conservation analysis
PDB id:
Name: Hydrolase (o-glycosyl)
Title: Structures of aromatic inhibitors of influenza virus neurami
Structure: Influenza a subtype n2 neuraminidase. Chain: a, b. Engineered: yes
Source: Influenza a virus (strain a/tokyo/3/19 organism_taxid: 380960. Strain: a/tokyo/3/1967 h2n2
Biol. unit: Tetramer (from PQS)
1.90Å     R-factor:   0.205    
Authors: M.J.Jedrzejas,M.Luo
Key ref:
M.J.Jedrzejas et al. (1995). Structures of aromatic inhibitors of influenza virus neuraminidase. Biochemistry, 34, 3144-3151. PubMed id: 7880809 DOI: 10.1021/bi00010a003
12-Dec-94     Release date:   31-Mar-95    
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Protein chains
Pfam   ArchSchema ?
P06820  (NRAM_I67A0) -  Neuraminidase
469 a.a.
388 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.  - 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: 10.1021/bi00010a003 Biochemistry 34:3144-3151 (1995)
PubMed id: 7880809  
Structures of aromatic inhibitors of influenza virus neuraminidase.
M.J.Jedrzejas, S.Singh, W.J.Brouillette, W.G.Laver, G.M.Air, M.Luo.
Neuraminidase (NA), a surface glycoprotein of influenza virus, is a potential target for design of antiinfluenza agents. The crystal structure of influenza virus neuraminidase showed that in the active site 11 residues are universally conserved among all strains known so far. Several potent inhibitors based on the carbohydrate compound 2-deoxy-2,3-didehydro-D-N-acetylneuraminic acid (DANA) have been shown to bind to the conserved active site and to reduce virus infection in animals when administered by nasal spray. Inhibitors of this type are, however, rapidly excreted from physiological systems and may not be effective in order to provide long-time protection. A new class of specific NA inhibitors, which are benzoic acid derivatives, has been designed on the basis of the three-dimensional structure of the NA-DANA complex and modeling of derivatives of 4-(acetylamino)benzoic acid in the NA active site. Intermediates were synthesized and were shown to moderately inhibit the NA activity and to bind to the NA active site as predicted. These rudimentary inhibitors, 4-(acetylamino)-3-hydroxy-5-nitrobenzoic acid, 4-(acetylamino)-3-hydroxy-5-aminobenzoic acid, and 4-(acetylamino)-3-aminobenzoic acid, and their X-ray structures in complexes with N2 (A/Tokyo/3/67) and B/Lee/40 neuraminidases have been analyzed. The coordinates of such inhibitors complexed with NA were used as the starting model for further design of more potent benzoic acid inhibitors. Because the active site residues of NA are invariant, the designed aromatic inhibitors have the potential to become an antiviral drug against all strains of influenza virus.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
18613071 Q.S.Du, R.B.Huang, Y.T.Wei, Z.W.Pang, L.Q.Du, and K.C.Chou (2009).
Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.
  J Comput Chem, 30, 295-304.  
17160999 I.M.Lagoja, and E.De Clercq (2008).
Anti-influenza virus agents: synthesis and mode of action.
  Med Res Rev, 28, 1.  
17623865 V.Ramensky, A.Sobol, N.Zaitseva, A.Rubinov, and V.Zosimov (2007).
A novel approach to local similarity of protein binding sites substantially improves computational drug design results.
  Proteins, 69, 349-357.  
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
15048822 J.M.Yang, and C.C.Chen (2004).
GEMDOCK: a generic evolutionary method for molecular docking.
  Proteins, 55, 288-304.  
15211517 T.Haselhorst, J.C.Wilson, R.J.Thomson, S.McAtamney, J.G.Menting, R.L.Coppel, and M.von Itzstein (2004).
Saturation transfer difference (STD) 1H-NMR experiments and in silico docking experiments to probe the binding of N-acetylneuraminic acid and derivatives to Vibrio cholerae sialidase.
  Proteins, 56, 346-353.  
12477861 J.W.Kim, M.Y.Seo, A.Shelat, C.S.Kim, T.W.Kwon, H.H.Lu, D.T.Moustakas, J.Sun, and J.H.Han (2003).
Structurally conserved amino Acid w501 is required for RNA helicase activity but is not essential for DNA helicase activity of hepatitis C virus NS3 protein.
  J Virol, 77, 571-582.  
11403085 A.Bianco, M.Brufani, F.Manna, and C.Melchioni (2001).
Synthesis of a carbocyclic sialic acid analogue for the inhibition of influenza virus neuraminidase.
  Carbohydr Res, 332, 23-31.  
11274459 B.J.Smith, P.M.Colman, M.Von Itzstein, B.Danylec, and J.N.Varghese (2001).
Analysis of inhibitor binding in influenza virus neuraminidase.
  Protein Sci, 10, 689-696.
PDB codes: 1f8b 1f8c 1f8d 1f8e
11276081 D.J.Diller, and K.M.Merz (2001).
High throughput docking for library design and library prioritization.
  Proteins, 43, 113-124.  
11381099 M.J.Jedrzejas (2001).
Pneumococcal virulence factors: structure and function.
  Microbiol Mol Biol Rev, 65, 187.  
12116409 Y.P.Pang, E.Perola, K.Xu, and F.G.Prendergast (2001).
EUDOC: a computer program for identification of drug interaction sites in macromolecules and drug leads from chemical databases.
  J Comput Chem, 22, 1750-1771.  
10389655 M.Hisaki, H.Imabori, M.Azuma, T.Suzutani, F.Iwakura, Y.Ohta, K.Kawanishi, Y.Ichigobara, M.Node, K.Nishide, I.Yoshida, and M.Ogasawara (1999).
Synthesis and anti-influenza virus activity of novel pyrimidine derivatives.
  Antiviral Res, 42, 121-137.  
10450950 W.J.Brouillette, V.R.Atigadda, M.Luo, G.M.Air, Y.S.Babu, and S.Bantia (1999).
Design of benzoic acid inhibitors of influenza neuraminidase containing a cyclic substitution for the N-acetyl grouping.
  Bioorg Med Chem Lett, 9, 1901-1906.  
  9835519 C.Y.Tai, P.A.Escarpe, R.W.Sidwell, M.A.Williams, W.Lew, H.Wu, C.U.Kim, and D.B.Mendel (1998).
Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071.
  Antimicrob Agents Chemother, 42, 3234-3241.  
9331424 R.C.Wade (1997).
'Flu' and structure-based drug design.
  Structure, 5, 1139-1145.  
8592707 M.J.Jedrzejas, S.Singh, W.J.Brouillette, G.M.Air, and M.Luo (1995).
A strategy for theoretical binding constant, Ki, calculations for neuraminidase aromatic inhibitors designed on the basis of the active site structure of influenza virus neuraminidase.
  Proteins, 23, 264-277.
PDB code: 1ing
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