Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 46, Pages 17736-17741Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0807142105
Keywords
crystallography; drug design
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Funding
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [HHSN266200700006C]
- University of St. Andrews [SCO13532]
- MRC [G0700805, MC_U117512711, G0600522] Funding Source: UKRI
- Medical Research Council [G0700805, G0600522, MC_U117512711] Funding Source: researchfish
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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.
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