Journal
STRUCTURE
Volume 21, Issue 8, Pages 1406-1416Publisher
CELL PRESS
DOI: 10.1016/j.str.2013.06.013
Keywords
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Funding
- NIH [R01 AI067417]
- Ruth L. Kirchstein Predoctoral Fellowship [F31 AI077323]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [W31-109-Eng-38]
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Hepatitis B virus (HBV) is a major cause of liver disease. Assembly of the HBV capsid is a critical step in virus production and an attractive target for new antiviral therapies. We determined the structure of HBV capsid in complex with AT-130, a member of the phenylpropenamide family of assembly effectors. AT-130 causes tertiary and quaternary structural changes but does not disrupt capsid structure. AT-130 binds a hydrophobic pocket that also accommodates the previously characterized heteroaryldihydropyrimidine compounds but favors a unique quasiequivalent location on the capsid surface. Thus, this pocket is a promiscuous drug-binding site and a likely target for different assembly effectors with a broad range of mechanisms of activity. That AT-130 successfully decreases virus production by increasing capsid assembly rate without disrupting capsid structure delineates a paradigm in antiviral design, that disrupting reaction timing is a viable strategy for assembly effectors of HBV and other viruses.
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