MRC National Institute for Medical Research, London
Science for Health
Structure of influenza hemagglutinin complex
24 November 2008
Influenza A virus membranes contain 3 proteins: hemagglutinin (HA), neuraminidase (NA), and the proton channel (M2). HA is responsible during the initial stages of infection for sialic acid-receptor binding and, after virus uptake into endosomes, for fusion of virus and cell membranes. The surface glycoprotein hemagglutinin 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. To address the need for new antivirals against influenza a number of studies have been made of inhibitors of the receptor binding or membrane fusion activities of HA.
Rupert Russell, Steven Gamblin (pictured) and their colleagues from NIMR's Division of Molecular Structure and the School of Biology, University of St Andrews, have determined the structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), and shown 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.
Our results show the value of structures of drug-hemagglutinin complexes in the design of drugs and in understanding mechanisms of their anti-viral activity.
Steve Gamblin
Original article
The research findings are published in full in:
Rupert J. Russell, Philip S. Kerry, David J. Stevens, David A. Steinhauer, Stephen R. Martin, Steven J. Gamblin and John J. Skehel
Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion
PNAS, epub ahead of print, Publisher abstract
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