Structure of Influenza Haemagglutinin in complex with an inhibitor of membrane fusion

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

Research output: Contribution to journalArticlepeer-review

215 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)17736-17741
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number46
DOIs
Publication statusPublished - 18 Nov 2008

Keywords

  • crystallography
  • drug design
  • CONFORMATIONAL-CHANGE
  • RECEPTOR-BINDING
  • A VIRUSES
  • PH
  • OSELTAMIVIR
  • AMANTADINE
  • NEURAMINIDASE
  • GLYCOPROTEIN
  • INFECTIVITY
  • EMERGENCE

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