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PDBsum entry 1nnc
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Hydrolase (o-glucosyl) PDB id
1nnc

 

 

 

 

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Contents
Protein chain
388 a.a. *
Ligands
NAG-NAG-BMA-MAN-
MAN-MAN
MAN
NAG ×2
ZMR
Metals
_CA
Waters ×197
* Residue conservation analysis
PDB id:
1nnc
Name: Hydrolase (o-glucosyl)
Title: Influenza virus neuraminidase subtype n9 (tern) complexed with 4- guanidino-neu5ac2en inhibitor
Structure: Neuraminidase n9. Chain: a. Synonym: sialidase, hydrolase (o-glycosyl). Ec: 3.2.1.18
Source: Influenza a virus (a/tern/australia/g70c/1975(h11n9)). Organism_taxid: 384509. Strain: a/tern/australia/g70c/75
Biol. unit: Tetramer (from PQS)
Resolution:
1.80Å     R-factor:   0.156    
Authors: J.N.Varghese,P.M.Colman
Key ref: J.N.Varghese et al. (1995). Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase. Protein Sci, 4, 1081-1087. PubMed id: 7549872 DOI: 10.1002/pro.5560040606
Date:
15-Mar-95     Release date:   03-Apr-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03472  (NRAM_I75A5) -  Neuraminidase from Influenza A virus (strain A/Tern/Australia/G70C/1975 H11N9)
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.

 

 
DOI no: 10.1002/pro.5560040606 Protein Sci 4:1081-1087 (1995)
PubMed id: 7549872  
 
 
Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase.
J.N.Varghese, V.C.Epa, P.M.Colman.
 
  ABSTRACT  
 
The three-dimensional X-ray structure of a complex of the potent neuraminidase inhibitor 4-guanidino-Neu5Ac2en and influenza virus neuraminidase (Subtype N9) has been obtained utilizing diffraction data to 1.8 A resolution. The interactions of the inhibitor, solvent water molecules, and the active site residues have been accurately determined. Six water molecules bound in the native structure have been displaced by the inhibitor, and the active site residues show no significant conformational changes on binding. Sialic acid, the natural substrate, binds in a half-chair conformation that is isosteric to the inhibitor. The conformation of the inhibitor in the active site of the X-ray structure concurs with that obtained by theoretical calculations and validates the structure-based design of the inhibitor. Comparison of known high-resolution structures of neuraminidase subtypes N2, N9, and B shows good structural conservation of the active site protein atoms, but the location of the water molecules in the respective active sites is less conserved. In particular, the environment of the 4-guanidino group of the inhibitor is strongly conserved and is the basis for the antiviral action of the inhibitor across all presently known influenza strains. Differences in the solvent structure in the active site may be related to variation in the affinities of inhibitors to different subtypes of neuraminidase.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
23250062 P.M.Colman (2013).
Early days in drug discovery by crystallography - personal recollections.
  Acta Crystallogr A, 69, 60-62.  
21248368 D.Tamura, N.Sugaya, M.Ozawa, R.Takano, M.Ichikawa, M.Yamazaki, C.Kawakami, H.Shimizu, R.Uehara, M.Kiso, E.Kawakami, K.Mitamura, and Y.Kawaoka (2011).
Frequency of drug-resistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors.
  Clin Infect Dis, 52, 432-437.  
20080770 M.Kiso, K.Takahashi, Y.Sakai-Tagawa, K.Shinya, S.Sakabe, Q.M.Le, M.Ozawa, Y.Furuta, and Y.Kawaoka (2010).
T-705 (favipiravir) activity against lethal H5N1 influenza A viruses.
  Proc Natl Acad Sci U S A, 107, 882-887.  
20538598 S.J.Gamblin, and J.J.Skehel (2010).
Influenza hemagglutinin and neuraminidase membrane glycoproteins.
  J Biol Chem, 285, 28403-28409.  
19950979 J.L.Paulsen, and A.C.Anderson (2009).
Scoring ensembles of docked protein:ligand interactions for virtual lead optimization.
  J Chem Inf Model, 49, 2813-2819.  
19754086 J.Michel, J.Tirado-Rives, and W.L.Jorgensen (2009).
Prediction of the water content in protein binding sites.
  J Phys Chem B, 113, 13337-13346.  
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.  
17939760 A.Moscona (2008).
Medical management of influenza infection.
  Annu Rev Med, 59, 397-413.  
18175324 M.Malaisree, T.Rungrotmongkol, P.Decha, P.Intharathep, O.Aruksakunwong, and S.Hannongbua (2008).
Understanding of known drug-target interactions in the catalytic pocket of neuraminidase subtype N1.
  Proteins, 71, 1908-1918.  
17961223 L.Yang, B.C.Allen, and R.S.Thomas (2007).
BMDExpress: a software tool for the benchmark dose analyses of genomic data.
  BMC Genomics, 8, 387.  
18049471 M.von Itzstein (2007).
The war against influenza: discovery and development of sialidase inhibitors.
  Nat Rev Drug Discov, 6, 967-974.  
17085491 O.Aruksakunwong, M.Malaisree, P.Decha, P.Sompornpisut, V.Parasuk, S.Pianwanit, and S.Hannongbua (2007).
On the lower susceptibility of oseltamivir to influenza neuraminidase subtype N1 than those in N2 and N9.
  Biophys J, 92, 798-807.  
17705169 P.A.Reece (2007).
Neuraminidase inhibitor resistance in influenza viruses.
  J Med Virol, 79, 1577-1586.  
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
16845429 D.H.Bunka, and P.G.Stockley (2006).
Aptamers come of age - at last.
  Nat Rev Microbiol, 4, 588-596.  
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.  
15918777 P.M.Colman (2005).
Zanamivir: an influenza virus neuraminidase inhibitor.
  Expert Rev Anti Infect Ther, 3, 191-199.  
16140748 T.Suzuki, T.Takahashi, C.T.Guo, K.I.Hidari, D.Miyamoto, H.Goto, Y.Kawaoka, and Y.Suzuki (2005).
Sialidase activity of influenza A virus in an endocytic pathway enhances viral replication.
  J Virol, 79, 11705-11715.  
15044728 P.Bonnet, and R.A.Bryce (2004).
Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.
  Protein Sci, 13, 946-957.  
15561823 S.J.Macdonald, K.G.Watson, R.Cameron, D.K.Chalmers, D.A.Demaine, R.J.Fenton, D.Gower, J.N.Hamblin, S.Hamilton, G.J.Hart, G.G.Inglis, B.Jin, H.T.Jones, D.B.McConnell, A.M.Mason, V.Nguyen, I.J.Owens, N.Parry, P.A.Reece, S.E.Shanahan, D.Smith, W.Y.Wu, and S.P.Tucker (2004).
Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen.
  Antimicrob Agents Chemother, 48, 4542-4549.  
14646315 T.Masuda, S.Yoshida, M.Arai, S.Kaneko, M.Yamashita, and T.Honda (2003).
Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives.
  Chem Pharm Bull (Tokyo), 51, 1386-1398.  
11991966 A.Molla, W.Kati, R.Carrick, K.Steffy, Y.Shi, D.Montgomery, N.Gusick, V.S.Stoll, K.D.Stewart, T.I.Ng, C.Maring, D.J.Kempf, and W.Kohlbrenner (2002).
In vitro selection and characterization of influenza A (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675.
  J Virol, 76, 5380-5386.  
11829724 J.L.McKimm-Breschkin (2002).
Neuraminidase inhibitors for the treatment and prevention of influenza.
  Expert Opin Pharmacother, 3, 103-112.  
12435681 M.Z.Wang, C.Y.Tai, and D.B.Mendel (2002).
Mechanism by which mutations at his274 alter sensitivity of influenza a virus n1 neuraminidase to oseltamivir carboxylate and zanamivir.
  Antimicrob Agents Chemother, 46, 3809-3816.  
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
11709315 L.V.Gubareva, R.G.Webster, and F.G.Hayden (2001).
Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants.
  Antimicrob Agents Chemother, 45, 3403-3408.  
9054567 A.Kohen, T.Jonsson, and J.P.Klinman (1997).
Effects of protein glycosylation on catalysis: changes in hydrogen tunneling and enthalpy of activation in the glucose oxidase reaction.
  Biochemistry, 36, 2603-2611.  
9342319 J.N.Varghese, P.M.Colman, A.van Donkelaar, T.J.Blick, A.Sahasrabudhe, and J.L.McKimm-Breschkin (1997).
Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases.
  Proc Natl Acad Sci U S A, 94, 11808-11812.
PDB code: 1mwe
  9094607 L.V.Gubareva, M.J.Robinson, R.C.Bethell, and R.G.Webster (1997).
Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en.
  J Virol, 71, 3385-3390.  
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 code is shown on the right.

 

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