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PDBsum entry 2qwi

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protein ligands metals links
Hydrolase PDB id
2qwi
Jmol
Contents
Protein chain
388 a.a. *
Ligands
NAG-NAG-BMA-MAN-
MAN-MAN
MAN
NAG ×2
G20
Metals
_CA
Waters ×196
* Residue conservation analysis
PDB id:
2qwi
Name: Hydrolase
Title: The x-ray structure of a complex of n-acetyl-4-guanidino-6- methyl(propyl)carboxamide-4,5-dihydro-2h-pyran-2-carboxylic wildtype tern n9 influenza virus neuraminidase
Structure: Neuraminidase. Chain: a. Fragment: residues 82 - 468. Synonym: sialidase. Engineered: yes. Other_details: integral membrane protein, membrane bound st cleaved by pronase, releasing fully active head with residu 468
Source: Influenza a virus. Organism_taxid: 11320. Strain: a/tern/australia/g70c/75. Expressed in: gallus gallus. Expression_system_taxid: 9031
Biol. unit: Homo-Tetramer (from PDB file)
Resolution:
2.00Å     R-factor:   0.184    
Authors: J.N.Varghese
Key ref:
J.N.Varghese et al. (1998). Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. Structure, 6, 735-746. PubMed id: 9655825 DOI: 10.1016/S0969-2126(98)00075-6
Date:
07-Apr-98     Release date:   11-Nov-98    
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: 10.1016/S0969-2126(98)00075-6 Structure 6:735-746 (1998)
PubMed id: 9655825  
 
 
Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase.
J.N.Varghese, P.W.Smith, S.L.Sollis, T.J.Blick, A.Sahasrabudhe, J.L.McKimm-Breschkin, P.M.Colman.
 
  ABSTRACT  
 
BACKGROUND: Inhibitors of the influenza virus neuraminidase have been shown to be effective antiviral agents in humans. Several studies have reported the selection of novel influenza strains when the virus is cultured with neuraminidase inhibitors in vitro. These resistant viruses have mutations either in the neuraminidase or in the viral haemagglutinin. Inhibitors in which the glycerol sidechain at position 6 of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) has been replaced by carboxamide-linked hydrophobic substituents have recently been reported and shown to select neuraminidase variants. This study seeks to clarify the structural and functional consequences of replacing the glycerol sidechain of the inhibitor with other chemical constituents. RESULTS: The neuraminidase variant Arg292-->Lys is modified in one of three arginine residues that encircle the carboxylate group of the substrate. The structure of this variant in complex with the carboxamide inhibitor used for its selection, and with other Neu5Ac2en analogues, is reported here at high resolution. The structural consequences of the mutation correlate with altered inhibitory activity of the compounds compared with wild-type neuraminidase. CONCLUSIONS: The Arg292-->Lys variant of influenza neuraminidase affects the binding of substrate by modification of the interaction with the substrate carboxylate. This may be one of the structural correlates of the reduced enzyme activity of the variant. Inhibitors that have replacements for the glycerol at position 6 are further affected in the Arg292-->Lys variant because of structural changes in the binding site that apparently raise the energy barrier for the conformational change in the enzyme required to accommodate such inhibitors. These results provide evidence that a general strategy for drug design when the target has a high mutation frequency is to design the inhibitor to be as closely related as possible to the natural ligands of the target.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. The chemical structures of influenza neuraminidase inhibitors: 1, sialic acid (N-acetylneuraminic acid (Neu5Ac)); 2, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en); 3, 4-amino-Neu5Ac2en; 4, Zanamivir, 4-guanidino-Neu5Ac2en; 5, 5-N-acetyl-4-guanidino-6-methyl(propyl) carboxamide-4,5-dihydro-2H-pyran-2-carboxylic acid; 6, 5-N-acetyl-4-amino-6-diethyl carboxamide-4,5-dihydro-2H-pyran-2-carboxylic acid; and 7, GS4071, 4-N-acetyl-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid.
 
  The above figure is reprinted by permission from Cell Press: Structure (1998, 6, 735-746) copyright 1998.  
  Figure was selected by an automated process.  

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.  
21326879 P.M.Schmidt, R.M.Attwood, P.G.Mohr, S.A.Barrett, and J.L.McKimm-Breschkin (2011).
A generic system for the expression and purification of soluble and stable influenza neuraminidase.
  PLoS One, 6, e16284.  
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
20129961 H.Zaraket, R.Saito, Y.Suzuki, T.Baranovich, C.Dapat, I.Caperig-Dapat, and H.Suzuki (2010).
Genetic makeup of amantadine-resistant and oseltamivir-resistant human influenza A/H1N1 viruses.
  J Clin Microbiol, 48, 1085-1092.  
20538598 S.J.Gamblin, and J.J.Skehel (2010).
Influenza hemagglutinin and neuraminidase membrane glycoproteins.
  J Biol Chem, 285, 28403-28409.  
19032598 H.Shen, F.Wang, Y.Zhang, Q.Huang, S.Xu, H.Hu, J.Yue, and H.Wang (2009).
A novel inhibitor of indole-3-glycerol phosphate synthase with activity against multidrug-resistant Mycobacterium tuberculosis.
  FEBS J, 276, 144-154.  
19254207 P.M.Colman (2009).
New antivirals and drug resistance.
  Annu Rev Biochem, 78, 95.  
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.  
18074341 A.D.Hill, and P.J.Reilly (2008).
A Gibbs free energy correlation for automated docking of carbohydrates.
  J Comput Chem, 29, 1131-1141.  
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
17426694 C.Y.Li, Q.Yu, Z.Q.Ye, Y.Sun, Q.He, X.M.Li, W.Zhang, J.Luo, X.Gu, X.Zheng, and L.Wei (2007).
A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir.
  Cell Res, 17, 357-362.  
  18252107 J.L.McKimm-Breschkin, P.W.Selleck, T.B.Usman, and M.A.Johnson (2007).
Reduced sensitivity of influenza A (H5N1) to oseltamivir.
  Emerg Infect Dis, 13, 1354-1357.  
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.  
16801417 A.S.Monto, J.L.McKimm-Breschkin, C.Macken, A.W.Hampson, A.Hay, A.Klimov, M.Tashiro, R.G.Webster, M.Aymard, F.G.Hayden, and M.Zambon (2006).
Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use.
  Antimicrob Agents Chemother, 50, 2395-2402.  
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.  
16940075 M.A.Rameix-Welti, F.Agou, P.Buchy, S.Mardy, J.T.Aubin, M.Véron, S.van der Werf, and N.Naffakh (2006).
Natural variation can significantly alter the sensitivity of influenza A (H5N1) viruses to oseltamivir.
  Antimicrob Agents Chemother, 50, 3809-3815.  
16575530 M.C.Mann, T.Islam, J.C.Dyason, P.Florio, C.J.Trower, R.J.Thomson, and M.von Itzstein (2006).
Unsaturated N-acetyl- D-glucosaminuronic acid glycosides as inhibitors of influenza virus sialidase.
  Glycoconj J, 23, 127-133.  
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.  
16915235 R.J.Russell, L.F.Haire, D.J.Stevens, P.J.Collins, Y.P.Lin, G.M.Blackburn, A.J.Hay, S.J.Gamblin, and J.J.Skehel (2006).
The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.
  Nature, 443, 45-49.
PDB codes: 2ht5 2ht7 2ht8 2htq 2htr 2htu 2htv 2htw 2hty 2hu0 2hu4
16007245 A.Moscona (2005).
Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease.
  J Clin Invest, 115, 1688-1698.  
15813662 J.L.McKimm-Breschkin (2005).
Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance.
  Treat Respir Med, 4, 107-116.  
15918777 P.M.Colman (2005).
Zanamivir: an influenza virus neuraminidase inhibitor.
  Expert Rev Anti Infect Ther, 3, 191-199.  
15337382 A.Moscona (2004).
Oseltamivir-resistant influenza?
  Lancet, 364, 733-734.  
12627392 M.Matrosovich, and H.D.Klenk (2003).
Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding.
  Rev Med Virol, 13, 85-97.  
11829724 J.L.McKimm-Breschkin (2002).
Neuraminidase inhibitors for the treatment and prevention of influenza.
  Expert Opin Pharmacother, 3, 103-112.  
12429084 P.M.Colman, and B.J.Smith (2002).
The trypanosomal trans-sialidase: two catalytic functions associated with one catalytic site.
  Structure, 10, 1466-1468.  
12177070 P.Vachette, E.Dainese, V.B.Vasyliev, P.Di Muro, M.Beltramini, D.I.Svergun, V.De Filippis, and B.Salvato (2002).
A key structural role for active site type 3 copper ions in human ceruloplasmin.
  J Biol Chem, 277, 40823-40831.  
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
11512153 C.L.Verlinde, V.Hannaert, C.Blonski, M.Willson, J.J.Périé, L.A.Fothergill-Gilmore, F.R.Opperdoes, M.H.Gelb, W.G.Hol, and P.A.Michels (2001).
Glycolysis as a target for the design of new anti-trypanosome drugs.
  Drug Resist Updat, 4, 50-65.  
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.  
10854663 F.M.Munoz, G.J.Galasso, J.M.Gwaltney, F.G.Hayden, B.Murphy, R.Webster, P.Wright, and R.B.Couch (2000).
Current research on influenza and other respiratory viruses: II international symposium.
  Antiviral Res, 46, 91.  
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.