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Journal of Virology, November 2006, p. 11055-11061, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00933-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Global Structural Changes in Hepatitis B Virus Capsids Induced by the Assembly Effector HAP1{triangledown} ,{dagger}

Christina R. Bourne,1 M. G. Finn,2 and Adam Zlotnick1*

Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 E. 10th Street, Oklahoma City, Oklahoma 73104,1 Department of Chemistry, The Scripps Research Institute, 10666 Torrey Pines Dr., La Jolla, California2

Received 8 May 2006/ Accepted 23 August 2006

Hepatitis B virus (HBV) is a leading cause of liver disease and hepatocellular carcinoma; over 400 million people are chronically infected with HBV. Specific anti-HBV treatments, like most antivirals, target enzymes that are similar to host proteins. Virus capsid protein has no human homolog, making its assembly a promising but undeveloped therapeutic target. HAP1 [methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate], a heteroaryldihydropyrimidine, is a potent HBV capsid assembly activator and misdirector. Knowledge of the structural basis for this activity would directly benefit the development of capsid-targeting therapeutic strategies. This report details the crystal structures of icosahedral HBV capsids with and without HAP1. We show that HAP1 leads to global structural changes by movements of subunits as connected rigid bodies. The observed movements cause the fivefold vertices to protrude from the liganded capsid, the threefold vertices to open, and the quasi-sixfold vertices to flatten, explaining the effects of HAP1 on assembled capsids and on the assembly process. We have identified a likely HAP1-binding site that bridges elements of secondary structure within a capsid-bound monomer, offering explanation for assembly activation. This site also interferes with interactions between capsid proteins, leading to quaternary changes and presumably assembly misdirection. These results demonstrate the plasticity of HBV capsids and the molecular basis for a tenable antiviral strategy.

* Corresponding author. Mailing address: 975 E. 10th Street, BRC 462B, Oklahoma City, OK 73104. Phone: (405) 271-9030. Fax: (405) 271-3910. E-mail: adam-zlotnick{at}ouhsc.edu.

{triangledown} Published ahead of print on 30 August 2006.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, November 2006, p. 11055-11061, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00933-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mannige, R. V., Brooks, C. L. III (2009). Geometric considerations in virus capsid size specificity, auxiliary requirements, and buckling. Proc. Natl. Acad. Sci. USA 106: 8531-8536 [Abstract] [Full Text]  
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