PDBsum entry 2ht8

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protein ligands links
Hydrolase PDB id
Protein chain
387 a.a. *
Waters ×91
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: N8 neuraminidase in complex with oseltamivir
Structure: Neuraminidase. Chain: a. Ec:
Source: Influenza a virus. Organism_taxid: 11320
Biol. unit: Tetramer (from PDB file)
2.40Å     R-factor:   0.252     R-free:   0.273
Authors: R.J.Russell,L.F.Haire,D.J.Stevens,P.J.Collins,Y.P.Lin,G.M.Bl A.J.Hay,S.J.Gamblin,J.J.Skehel
Key ref:
R.J.Russell et al. (2006). The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature, 443, 45-49. PubMed id: 16915235 DOI: 10.1038/nature05114
25-Jul-06     Release date:   05-Sep-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q07599  (NRAM_I63A3) -  Neuraminidase
470 a.a.
387 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: 10.1038/nature05114 Nature 443:45-49 (2006)
PubMed id: 16915235  
The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.
R.J.Russell, L.F.Haire, D.J.Stevens, P.J.Collins, Y.P.Lin, G.M.Blackburn, A.J.Hay, S.J.Gamblin, J.J.Skehel.
The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.
  Selected figure(s)  
Figure 2.
Figure 2: Molecular surfaces of group-1 and group-2 neuraminidases with bound oseltamivir showing the 150-cavity in the group-1 structure that arises because of the distinct conformation of the 150-loop. a, b, N1 (a; green) and N9 (b; yellow) shown in surface representation with the protein main chain shown in 'worm' representation. c, Superposition of the active sites of apo-N1 (green) and N1 complexed with oseltamivir (blue). Part of the electron density map from a low-resolution (5.5 Å) difference Fourier calculated between apo-N1 and oseltamivir-bound N1 data sets is shown in blue to indicate the position of the 150-cavity.
Figure 3.
Figure 3: Oseltamivir binding to the active sites of group-1 neuraminidases. a, Superposition of the active sites of N8 after a 30-min soak (dark blue) and a 3-day soak (cyan) with 20 M oseltamivir. There are small changes in the position of Glu 119 and the inhibitor when the 150-loop closes after the longer soaking time. b, Superposition of the active sites of N8 with bound oseltamivir after the 3-day soak with 20 M inhibitor (cyan) with N1 soaked for 30 min in 0.5 mM inhibitor (green). In this case, the structures of the two different subtypes of neuraminidase from group-1 are remarkably similar.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2006, 443, 45-49) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21489803 A.Albohy, S.Mohan, R.B.Zheng, B.M.Pinto, and C.W.Cairo (2011).
Inhibitor selectivity of a new class of oseltamivir analogs against viral neuraminidase over human neuraminidase enzymes.
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21303099 C.J.Woods, M.Malaisree, S.Hannongbua, and A.J.Mulholland (2011).
A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies.
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21305698 H.Hinou, R.Miyoshi, Y.Takasu, H.Kai, M.Kurogochi, S.Arioka, X.D.Gao, N.Miura, N.Fujitani, S.Omoto, T.Yoshinaga, T.Fujiwara, T.Noshi, H.Togame, H.Takemoto, and S.Nishimura (2011).
A strategy for neuraminidase inhibitors using mechanism-based labeling information.
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21211019 J.Abdussamad, and S.Aris-Brosou (2011).
The nonadaptive nature of the H1N1 2009 Swine Flu pandemic contrasts with the adaptive facilitation of transmission to a new host.
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21373190 J.Li, H.Zu Dohna, C.J.Cardona, J.Miller, and T.E.Carpenter (2011).
Emergence and genetic variation of neuraminidase stalk deletions in avian influenza viruses.
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Identification of critical residues of influenza neuraminidase in viral particle release.
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21443905 M.Niikura, N.Bance, S.Mohan, and B.Mario Pinto (2011).
Replication inhibition activity of carbocycles related to oseltamivir on influenza A virus in vitro.
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20517627 M.Shu, Z.Lin, Y.Zhang, Y.Wu, H.Mei, and Y.Jiang (2011).
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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.
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Design, synthesis and biological activity of thiazolidine-4-carboxylic acid derivatives as novel influenza neuraminidase inhibitors.
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20170556 A.Ghosh, A.Nandy, and P.Nandy (2010).
Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase.
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20941447 H.Ge, Y.F.Wang, J.Xu, Q.Gu, H.B.Liu, P.G.Xiao, J.Zhou, Y.Liu, Z.Yang, and H.Su (2010).
Anti-influenza agents from Traditional Chinese Medicine.
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20155919 J.C.Sung, A.W.Van Wynsberghe, R.E.Amaro, W.W.Li, and J.A.McCammon (2010).
Role of secondary sialic acid binding sites in influenza N1 neuraminidase.
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20522774 J.D.Bloom, L.I.Gong, and D.Baltimore (2010).
Permissive secondary mutations enable the evolution of influenza oseltamivir resistance.
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20427241 J.D.Durrant, and J.A.McCammon (2010).
Potential drug-like inhibitors of Group 1 influenza neuraminidase identified through computer-aided drug design.
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20383144 K.Das, J.M.Aramini, L.C.Ma, R.M.Krug, and E.Arnold (2010).
Structures of influenza A proteins and insights into antiviral drug targets.
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  20885781 L.Le, E.H.Lee, D.J.Hardy, T.N.Truong, and K.Schulten (2010).
Molecular dynamics simulations suggest that electrostatic funnel directs binding of Tamiflu to influenza N1 neuraminidases.
  PLoS Comput Biol, 6, 0.  
19828755 M.C.Giocondi, F.Ronzon, M.C.Nicolai, P.Dosset, P.E.Milhiet, M.Chevalier, and C.Le Grimellec (2010).
Organization of influenza A virus envelope at neutral and low pH.
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20434570 M.Fourment, J.T.Wood, A.J.Gibbs, and M.J.Gibbs (2010).
Evolutionary dynamics of the N1 neuraminidases of the main lineages of influenza A viruses.
  Mol Phylogenet Evol, 56, 526-535.  
20523902 N.A.Ilyushina, J.P.Seiler, J.E.Rehg, R.G.Webster, and E.A.Govorkova (2010).
Effect of neuraminidase inhibitor-resistant mutations on pathogenicity of clade 2.2 A/Turkey/15/06 (H5N1) influenza virus in ferrets.
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20852645 Q.Li, J.Qi, W.Zhang, C.J.Vavricka, Y.Shi, J.Wei, E.Feng, J.Shen, J.Chen, D.Liu, J.He, J.Yan, H.Liu, H.Jiang, M.Teng, X.Li, and G.F.Gao (2010).
The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site.
  Nat Struct Mol Biol, 17, 1266-1268.
PDB code: 3nss
20808434 R.Patil, S.Das, A.Stanley, L.Yadav, A.Sudhakar, and A.K.Varma (2010).
Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing.
  PLoS One, 5, e12029.  
20538598 S.J.Gamblin, and J.J.Skehel (2010).
Influenza hemagglutinin and neuraminidase membrane glycoproteins.
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19889765 S.Munier, T.Larcher, F.Cormier-Aline, D.Soubieux, B.Su, L.Guigand, B.Labrosse, Y.Cherel, P.Quéré, D.Marc, and N.Naffakh (2010).
A genetically engineered waterfowl influenza virus with a deletion in the stalk of the neuraminidase has increased virulence for chickens.
  J Virol, 84, 940-952.  
  21081911 S.Rudrawar, J.C.Dyason, M.A.Rameix-Welti, F.J.Rose, P.S.Kerry, R.J.Russell, S.van der Werf, R.J.Thomson, N.Naffakh, and M.von Itzstein (2010).
Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase.
  Nat Commun, 1, 113.
PDB codes: 3o9j 3o9k
20521684 T.Goletić, A.Gagić, E.Residbegović, A.Kustura, A.Kavazović, V.Savić, T.Harder, E.Starick, and S.Prasović (2010).
Highly pathogenic avian influenza virus subtype H5N1 in mute swans (Cygnus olor) in Central Bosnia.
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20139160 T.H.Chang, F.L.Hsieh, T.P.Ko, K.H.Teng, P.H.Liang, and A.H.Wang (2010).
Structure of a heterotetrameric geranyl pyrophosphate synthase from mint (Mentha piperita) reveals intersubunit regulation.
  Plant Cell, 22, 454-467.
PDB codes: 3kra 3krc 3krf 3kro 3krp
20028826 V.M.Deyde, T.G.Sheu, A.A.Trujillo, M.Okomo-Adhiambo, R.Garten, A.I.Klimov, and L.V.Gubareva (2010).
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Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial.
  PLoS Med, 7, e1000362.  
20410266 Y.P.Lin, V.Gregory, P.Collins, J.Kloess, S.Wharton, N.Cattle, A.Lackenby, R.Daniels, and A.Hay (2010).
Neuraminidase receptor binding variants of human influenza A(H3N2) viruses resulting from substitution of aspartic acid 151 in the catalytic site: a role in virus attachment?
  J Virol, 84, 6769-6781.  
19651908 A.C.Hurt, J.K.Holien, and I.G.Barr (2009).
In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
  Antimicrob Agents Chemother, 53, 4433-4440.  
19641000 A.C.Hurt, J.K.Holien, M.Parker, A.Kelso, and I.G.Barr (2009).
Zanamivir-resistant influenza viruses with a novel neuraminidase mutation.
  J Virol, 83, 10366-10373.  
  19236725 A.C.Mishra, S.S.Cherian, A.K.Chakrabarti, S.D.Pawar, S.M.Jadhav, B.Pal, S.Raut, S.Koratkar, and S.S.Kode (2009).
A unique influenza A (H5N1) virus causing a focal poultry outbreak in 2007 in Manipur, India.
  Virol J, 6, 26.  
19924254 A.K.Chakrabarti, S.D.Pawar, S.S.Cherian, S.S.Koratkar, S.M.Jadhav, B.Pal, S.Raut, V.Thite, S.S.Kode, S.S.Keng, B.J.Payyapilly, J.Mullick, and A.C.Mishra (2009).
Characterization of the influenza A H5N1 viruses of the 2008-09 outbreaks in India reveals a third introduction and possible endemicity.
  PLoS One, 4, e7846.  
19586376 A.S.Monto (2009).
Implications of antiviral resistance of influenza viruses.
  Clin Infect Dis, 48, 397-399.  
20041119 B.Su, S.Wurtzer, M.A.Rameix-Welti, D.Dwyer, S.van der Werf, N.Naffakh, F.Clavel, and B.Labrosse (2009).
Enhancement of the influenza A hemagglutinin (HA)-mediated cell-cell fusion and virus entry by the viral neuraminidase (NA).
  PLoS One, 4, e8495.  
19349520 E.A.Govorkova, N.A.Ilyushina, J.L.McClaren, T.S.Naipospos, B.Douangngeun, and R.G.Webster (2009).
Susceptibility of highly pathogenic H5N1 influenza viruses to the neuraminidase inhibitor oseltamivir differs in vitro and in a mouse model.
  Antimicrob Agents Chemother, 53, 3088-3096.  
19133796 I.Stephenson, J.Democratis, A.Lackenby, T.McNally, J.Smith, M.Pareek, J.Ellis, A.Bermingham, K.Nicholson, and M.Zambon (2009).
Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children.
  Clin Infect Dis, 48, 389-396.  
19207419 J.D.Durrant, R.E.Amaro, and J.A.McCammon (2009).
AutoGrow: a novel algorithm for protein inhibitor design.
  Chem Biol Drug Des, 73, 168-178.  
19458903 J.Uhlendorff, T.Matrosovich, H.D.Klenk, and M.Matrosovich (2009).
Functional significance of the hemadsorption activity of influenza virus neuraminidase and its alteration in pandemic viruses.
  Arch Virol, 154, 945-957.  
  20029609 L.Le, E.Lee, K.Schulten, and T.N.Truong (2009).
Molecular modeling of swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1 neuraminidases bound to Tamiflu and Relenza.
  PLoS Curr, 1, RRN1015.  
19528219 M.A.Rameix-Welti, M.L.Zarantonelli, D.Giorgini, C.Ruckly, M.Marasescu, S.van der Werf, J.M.Alonso, N.Naffakh, and M.K.Taha (2009).
Influenza A virus neuraminidase enhances meningococcal adhesion to epithelial cells through interaction with sialic acid-containing meningococcal capsules.
  Infect Immun, 77, 3588-3595.  
19461872 M.Lawrenz, R.Baron, and J.A.McCammon (2009).
Independent-Trajectories Thermodynamic-Integration Free-Energy Changes for Biomolecular Systems: Determinants of H5N1 Avian Influenza Virus Neuraminidase Inhibition by Peramivir.
  J Chem Theory Comput, 5, 1106-1116.  
  19309695 N.X.Wang, and J.J.Zheng (2009).
Computational studies of H5N1 influenza virus resistance to oseltamivir.
  Protein Sci, 18, 707-715.  
19187561 P.K.Dhar, C.S.Thwin, K.Tun, Y.Tsumoto, S.Maurer-Stroh, F.Eisenhaber, and U.Surana (2009).
Synthesizing non-natural parts from natural genomic template.
  J Biol Eng, 3, 2.  
19254207 P.M.Colman (2009).
New antivirals and drug resistance.
  Annu Rev Biochem, 78, 95.  
19296611 R.E.Amaro, X.Cheng, I.Ivanov, D.Xu, and J.A.McCammon (2009).
Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations.
  J Am Chem Soc, 131, 4702-4709.  
19428126 R.M.Krug, and J.M.Aramini (2009).
Emerging antiviral targets for influenza A virus.
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19381279 S.Khurana, A.L.Suguitan, Y.Rivera, C.P.Simmons, A.Lanzavecchia, F.Sallusto, J.Manischewitz, L.R.King, K.Subbarao, and H.Golding (2009).
Antigenic fingerprinting of H5N1 avian influenza using convalescent sera and monoclonal antibodies reveals potential vaccine and diagnostic targets.
  PLoS Med, 6, e1000049.  
19457254 S.Maurer-Stroh, J.Ma, R.T.Lee, F.L.Sirota, and F.Eisenhaber (2009).
Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites.
  Biol Direct, 4, 18; discussion 18.  
19580433 V.M.Deyde, and L.V.Gubareva (2009).
Influenza genome analysis using pyrosequencing method: current applications for a moving target.
  Expert Rev Mol Diagn, 9, 493-509.  
19124660 V.M.Deyde, T.Nguyen, R.A.Bright, A.Balish, B.Shu, S.Lindstrom, A.I.Klimov, and L.V.Gubareva (2009).
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19082878 Y.Pei, J.Swinton, D.Ojkic, and S.Sharif (2009).
Genetic characterization of two low pathogenic avian influenza virus H5N1 isolates from Ontario, Canada.
  Virus Genes, 38, 149-154.  
19865525 Z.W.Yang, X.M.Wu, L.J.Zhou, and G.Yang (2009).
A proline-based neuraminidase inhibitor: DFT studies on the zwitterion conformation, stability and formation.
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The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study.
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A broad spectrum, one-step reverse-transcription PCR amplification of the neuraminidase gene from multiple subtypes of influenza A virus.
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18978531 A.Lackenby, C.I.Thompson, and J.Democratis (2008).
The potential impact of neuraminidase inhibitor resistant influenza.
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18660801 E.Obayashi, H.Yoshida, F.Kawai, N.Shibayama, A.Kawaguchi, K.Nagata, J.R.Tame, and S.Y.Park (2008).
The structural basis for an essential subunit interaction in influenza virus RNA polymerase.
  Nature, 454, 1127-1131.
PDB code: 2znl
18328578 J.Beigel, and M.Bray (2008).
Current and future antiviral therapy of severe seasonal and avian influenza.
  Antiviral Res, 78, 91.  
18214665 K.Ray, V.A.Potdar, S.S.Cherian, S.D.Pawar, S.M.Jadhav, S.R.Waregaonkar, A.A.Joshi, and A.C.Mishra (2008).
Characterization of the complete genome of influenza A (H5N1) virus isolated during the 2006 outbreak in poultry in India.
  Virus Genes, 36, 345-353.  
18558668 L.S.Cheng, R.E.Amaro, D.Xu, W.W.Li, P.W.Arzberger, and J.A.McCammon (2008).
Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.
  J Med Chem, 51, 3878-3894.  
18654625 M.A.Rameix-Welti, V.Enouf, F.Cuvelier, P.Jeannin, and S.van der Werf (2008).
Enzymatic properties of the neuraminidase of seasonal H1N1 influenza viruses provide insights for the emergence of natural resistance to oseltamivir.
  PLoS Pathog, 4, e1000103.  
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.  
18205727 M.R.Landon, R.E.Amaro, R.Baron, C.H.Ngan, D.Ozonoff, J.A.McCammon, and S.Vajda (2008).
Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble.
  Chem Biol Drug Des, 71, 106-116.  
18706999 M.von Itzstein (2008).
Disease-associated carbohydrate-recognising proteins and structure-based inhibitor design.
  Curr Opin Struct Biol, 18, 558-566.  
18295610 M.von Itzstein (2008).
Avian influenza virus, a very sticky situation.
  Curr Opin Chem Biol, 12, 102-108.  
18725448 N.A.Ilyushina, A.Hay, N.Yilmaz, A.C.Boon, R.G.Webster, and E.A.Govorkova (2008).
Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice.
  Antimicrob Agents Chemother, 52, 3889-3897.  
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
18715929 X.Xu, X.Zhu, R.A.Dwek, J.Stevens, and I.A.Wilson (2008).
Structural characterization of the 1918 influenza virus H1N1 neuraminidase.
  J Virol, 82, 10493-10501.
PDB codes: 3b7e 3beq
17855542 H.L.Yen, N.A.Ilyushina, R.Salomon, E.Hoffmann, R.G.Webster, and E.A.Govorkova (2007).
Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo.
  J Virol, 81, 12418-12426.  
  18252107 J.L.McKimm-Breschkin, P.W.Selleck, T.B.Usman, and M.A.Johnson (2007).
Reduced sensitivity of influenza A (H5N1) to oseltamivir.
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Avian influenza virus (H5N1): a threat to human health.
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The war against influenza: discovery and development of sialidase inhibitors.
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17705169 P.A.Reece (2007).
Neuraminidase inhibitor resistance in influenza viruses.
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Antiviral agents active against influenza A viruses.
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Viral enzymes.
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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.