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PDBsum entry 1l7f

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protein ligands metals links
Hydrolase PDB id
1l7f
Jmol
Contents
Protein chain
388 a.a. *
Ligands
NAG-NAG-BMA-MAN-
MAN-MAN-MAN
NAG-NAG
NAG
BCZ
GOL ×3
Metals
_CA ×2
Waters ×642
* Residue conservation analysis
PDB id:
1l7f
Name: Hydrolase
Title: Crystal structure of influenza virus neuraminidase in comple bcx-1812
Structure: Neuraminidase. Chain: a. Fragment: integral membrane protein, membrane stalk cleaved pronase releasing fully active residues 82-468. Ec: 3.2.1.18
Source: Influenza a virus. Organism_taxid: 11320. Strain: a/nws/tern/australia/g70c/75
Biol. unit: Tetramer (from PDB file)
Resolution:
1.80Å     R-factor:   0.153     R-free:   0.187
Authors: B.J.Smith,J.L.Mckimm-Breshkin,M.Mcdonald,R.T.Fernley,J.N.Var P.M.Colman
Key ref: B.J.Smith et al. (2002). Structural studies of the resistance of influenza virus neuramindase to inhibitors. J Med Chem, 45, 2207-2212. PubMed id: 12014958 DOI: 10.1021/jm010528u
Date:
15-Mar-02     Release date:   29-May-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03472  (NRAM_I75A5) -  Neuraminidase
Seq:
Struc:
470 a.a.
388 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: 10.1021/jm010528u J Med Chem 45:2207-2212 (2002)
PubMed id: 12014958  
 
 
Structural studies of the resistance of influenza virus neuramindase to inhibitors.
B.J.Smith, J.L.McKimm-Breshkin, M.McDonald, R.T.Fernley, J.N.Varghese, P.M.Colman.
 
  ABSTRACT  
 
Zanamivir and oseltamivir, specific inhibitors of influenza virus neuraminidase, have significantly different characteristics in resistance studies. In both cases resistance is known to arise through mutations in either the hemagglutinin or neuraminidase surface proteins. A new inhibitor under development by Biocryst Pharmaceuticals, BCX-1812, has both a guanidino group, as in zanamivir, and a bulky hydrophobic group, as in oseltamivir. Using influenza A/NWS/Tern/Australia/G70C/75 (H1N9), neuraminidase variants E119G and R292K have previously been selected by different inhibitors. The sensitivity of these variants to BCX-1812 has now been measured and found in both cases to be intermediate between those of zanamivir and oseltamivir. In addition, the X-ray crystal structures of the complexes of BCX-1812 with the wild type and the two mutant neuraminidases were determined. The ligand is bound in an identical manner in each structure, with a rearrangement of the side chain of E276 from its ligand-free position. A structural explanation of the mechanism of resistance of BCX-1812, relative to zanamivir and oseltamivir in particular, is provided.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20695427 A.J.Oakley, S.Barrett, T.S.Peat, J.Newman, V.A.Streltsov, L.Waddington, T.Saito, M.Tashiro, and J.L.McKimm-Breschkin (2010).
Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
  J Med Chem, 53, 6421-6431.
PDB codes: 3k36 3k37 3k38 3k39 3k3a
20519385 E.A.Govorkova, N.A.Ilyushina, B.M.Marathe, J.L.McClaren, and R.G.Webster (2010).
Competitive fitness of oseltamivir-sensitive and -resistant highly pathogenic H5N1 influenza viruses in a ferret model.
  J Virol, 84, 8042-8050.  
20350949 K.Sleeman, V.P.Mishin, V.M.Deyde, Y.Furuta, A.I.Klimov, and L.V.Gubareva (2010).
In Vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses.
  Antimicrob Agents Chemother, 54, 2517-2524.  
20186344 Q.S.Du, R.B.Huang, S.Q.Wang, and K.C.Chou (2010).
Designing inhibitors of M2 proton channel against H1N1 swine influenza virus.
  PLoS One, 5, e9388.  
20538598 S.J.Gamblin, and J.J.Skehel (2010).
Influenza hemagglutinin and neuraminidase membrane glycoproteins.
  J Biol Chem, 285, 28403-28409.  
19062293 N.Tokuriki, C.J.Oldfield, V.N.Uversky, I.N.Berezovsky, and D.S.Tawfik (2009).
Do viral proteins possess unique biophysical features?
  Trends Biochem Sci, 34, 53-59.  
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.  
19703025 V.Kairys, M.K.Gilson, V.Lather, C.A.Schiffer, and M.X.Fernandes (2009).
Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.
  Chem Biol Drug Des, 74, 234-245.  
17939760 A.Moscona (2008).
Medical management of influenza infection.
  Annu Rev Med, 59, 397-413.  
18480754 P.J.Collins, L.F.Haire, Y.P.Lin, J.Liu, R.J.Russell, P.A.Walker, J.J.Skehel, S.R.Martin, A.J.Hay, and S.J.Gamblin (2008).
Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants.
  Nature, 453, 1258-1261.
PDB codes: 3ckz 3cl0 3cl2
18049471 M.von Itzstein (2007).
The war against influenza: discovery and development of sialidase inhibitors.
  Nat Rev Drug Discov, 6, 967-974.  
17202791 N.Hirayama (2007).
[Docking method for drug discovery]
  Yakugaku Zasshi, 127, 113-122.  
17705169 P.A.Reece (2007).
Neuraminidase inhibitor resistance in influenza viruses.
  J Med Virol, 79, 1577-1586.  
17522206 T.W.Lin, C.W.Lo, S.Y.Lai, R.J.Fan, C.J.Lo, Y.M.Chou, R.Thiruvengadam, A.H.Wang, and M.Y.Wang (2007).
Chicken heat shock protein 90 is a component of the putative cellular receptor complex of infectious bursal disease virus.
  J Virol, 81, 8730-8741.  
16929094 B.J.Smith, T.Huyton, R.P.Joosten, J.L.McKimm-Breschkin, J.G.Zhang, C.S.Luo, M.Z.Lou, N.E.Labrou, and T.P.Garrett (2006).
Structure of a calcium-deficient form of influenza virus neuraminidase: implications for substrate binding.
  Acta Crystallogr D Biol Crystallogr, 62, 947-952.
PDB code: 2b8h
16912325 H.L.Yen, E.Hoffmann, G.Taylor, C.Scholtissek, A.S.Monto, R.G.Webster, and E.A.Govorkova (2006).
Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses.
  J Virol, 80, 8787-8795.  
15073366 A.E.Smith, and A.Helenius (2004).
How viruses enter animal cells.
  Science, 304, 237-242.  
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.