Home LiteratureArticle Details
PMID: 19004788 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 46 ·2008-11-18 ·Pages 17736-41

Russell RJ, Kerry PS, Stevens DJ, Steinhauer DA, Martin SR, Gamblin SJ, Skehel JJ

Abstract

The influenza surface glycoprotein hemagglutinin (HA) is a potential target for antiviral drugs because of its key roles in the initial stages of infection: receptor binding and the fusion of virus and cell membranes. The structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), shows that the inhibitor binds in a hydrophobic pocket formed at an interface between HA monomers. Occupation of this site by TBHQ stabilizes the neutral pH structure through intersubunit and intrasubunit interactions that presumably inhibit the conformational rearrangements required for membrane fusion. The nature of the binding site suggests routes for the chemical modification of TBHQ that could lead to the development of more potent inhibitors of membrane fusion and potential anti-influenza drugs.

MeSH Terms
Binding Sites Fluorometry Hemagglutinin Glycoproteins, Influenza Virus/chemistry Hydrogen-Ion Concentration/drug effects Hydroquinones/chemistry,pharmacology Membrane Fusion/drug effects Phylogeny Protein Multimerization/drug effects Protein Structure, Secondary Protein Subunits/chemistry Substrate Specificity/drug effects
Chemicals
Hemagglutinin Glycoproteins, Influenza Virus Hydroquinones Protein Subunits 2-tert-butylhydroquinone
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Russell Rupert J
Interdisciplinary Center for Human and Avian Influenza Research, School of Biology, University of St. Andrews, Fife KY16 9ST, United Kingdom. rjmr@st-andrews.ac.uk
Kerry Philip S
Stevens David J
Steinhauer David A
Martin Stephen R
Gamblin Steven J
Skehel John J
References (37)
37 references, click to expand
  1. The CCP4 suite: programs for protein crystallography.
    Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3 PMID: 15299374
  2. Phylogenetic trees: visualizing, customizing and detecting incongruence.
    Bioinformatics. 2005 Oct 1;21(19):3801-2 PMID: 16030069
  3. Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones.
    Biochemistry. 1993 Mar 30;32(12):2967-78 PMID: 8457561
  4. Influenza-virus-liposome lipid mixing is leaky and largely insensitive to the material properties of the target membrane.
    Biochemistry. 1996 Apr 16;35(15):4956-65 PMID: 8664288
  5. Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine.
    Curr Top Microbiol Immunol. 1992;176:119-30 PMID: 1600749
  6. The molecular basis of the specific anti-influenza action of amantadine.
    EMBO J. 1985 Nov;4(11):3021-4 PMID: 4065098
  7. H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes.
    Virology. 2004 Aug 1;325(2):287-96 PMID: 15246268
  8. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.
    J Am Chem Soc. 1997 Jan 29;119(4):681-90 PMID: 16526129
  9. Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusion.
    Virology. 2008 Jan 20;370(2):403-14 PMID: 17936324
  10. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.
    Annu Rev Biochem. 2000;69:531-69 PMID: 10966468
  11. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir.
    J Infect Dis. 2001 Feb 15;183(4):523-31 PMID: 11170976
  12. Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants.
    Antiviral Res. 2006 Jul;70(3):121-31 PMID: 16516984
  13. Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: irreversible inhibition of infectivity.
    J Virol. 1997 Nov;71(11):8808-20 PMID: 9343241
  14. Automated analysis of interatomic contacts in proteins.
    Bioinformatics. 1999 Apr;15(4):327-32 PMID: 10320401
  15. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution.
    Nature. 1981 Jan 29;289(5796):366-73 PMID: 7464906
  16. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls.
    J Virol. 2005 Mar;79(5):2814-22 PMID: 15709000
  17. Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine.
    Bioorg Med Chem Lett. 2002 Dec 2;12(23):3379-82 PMID: 12419365
  18. The M2 proton channels of influenza A and B viruses.
    J Biol Chem. 2006 Apr 7;281(14):8997-9000 PMID: 16407184
  19. Amantadine selection of a mutant influenza virus containing an acid-stable hemagglutinin glycoprotein: evidence for virus-specific regulation of the pH of glycoprotein transport vesicles.
    Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11525-9 PMID: 1763066
  20. Rational design of potent sialidase-based inhibitors of influenza virus replication.
    Nature. 1993 Jun 3;363(6428):418-23 PMID: 8502295
  21. Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity.
    Nature. 1983 Jul 7-13;304(5921):76-8 PMID: 6191220
  22. N- and C-terminal residues combine in the fusion-pH influenza hemagglutinin HA(2) subunit to form an N cap that terminates the triple-stranded coiled coil.
    Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8967-72 PMID: 10430879
  23. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability.
    Nat Protoc. 2007;2(9):2212-21 PMID: 17853878
  24. Improved methods for building protein models in electron density maps and the location of errors in these models.
    Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9 PMID: 2025413
  25. X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs.
    Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11181-6 PMID: 11562490
  26. Epidemiology of HIV/AIDS--United States, 1981-2005.
    MMWR Morb Mortal Wkly Rep. 2006 Jun 2;55(21):589-92 PMID: 16741494
  27. Structure of influenza haemagglutinin at the pH of membrane fusion.
    Nature. 1994 Sep 1;371(6492):37-43 PMID: 8072525
  28. Ligand binding affinity determined by temperature-dependent circular dichroism: cyclin-dependent kinase 2 inhibitors.
    Anal Biochem. 2005 Oct 15;345(2):187-97 PMID: 16140252
  29. Viral membrane fusion.
    Nat Struct Mol Biol. 2008 Jul;15(7):690-8 PMID: 18596815
  30. A revision of the system of nomenclature for influenza viruses: a WHO memorandum.
    Bull World Health Organ. 1980;58(4):585-91 PMID: 6969132
  31. PHENIX: building new software for automated crystallographic structure determination.
    Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54 PMID: 12393927
  32. Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo.
    Antiviral Res. 2002 May;54(2):79-88 PMID: 12062393
  33. Antiviral agents active against influenza A viruses.
    Nat Rev Drug Discov. 2006 Dec;5(12):1015-25 PMID: 17139286
  34. Structure of influenza virus haemagglutinin complexed with a neutralizing antibody.
    Nature. 1995 Jul 6;376(6535):92-4 PMID: 7596443
  35. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic.
    J Antimicrob Chemother. 2005 Feb;55 Suppl 1:i5-i21 PMID: 15709056
  36. Phaser crystallographic software.
    J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674 PMID: 19461840
  37. The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype).
    Cell. 1982 Dec;31(2 Pt 1):417-27 PMID: 6186384
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0807142105
Email
rjmr@st-andrews.ac.uk
Published
2008-11-18
Epub
2008-00-12
Pages
17736-41
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2584702
Subset
IM
Grants
Medical Research Council · G0600522 · United Kingdom
Medical Research Council · G0700805 · United Kingdom
NIAID NIH HHS · HHSN266200700006C · United States
Medical Research Council · MC_U117512711 · United Kingdom
Databases
PDB
3EYJ, 3EYK, 3EYM
Corrections
CommentIn
PMID: 19033206
External Links
PubMed source DOI: 10.1073/pnas.0807142105 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2