2g33: Difference between revisions
New page: left|200px<br /><applet load="2g33" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g33, resolution 3.960Å" /> '''Human Hepatitis B V... |
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[[Image:2g33.gif|left|200px]]<br /><applet load="2g33" size=" | [[Image:2g33.gif|left|200px]]<br /><applet load="2g33" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2g33, resolution 3.960Å" /> | caption="2g33, resolution 3.960Å" /> | ||
'''Human Hepatitis B Virus T=4 capsid, strain adyw'''<br /> | '''Human Hepatitis B Virus T=4 capsid, strain adyw'''<br /> | ||
==Overview== | ==Overview== | ||
Hepatitis B virus (HBV) is a leading cause of liver disease and | 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-dihydropyrimidin e-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. | ||
==About this Structure== | ==About this Structure== | ||
2G33 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Hepatitis_b_virus_subtype_adw Hepatitis b virus subtype adw]. Full crystallographic information is available from [http:// | 2G33 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Hepatitis_b_virus_subtype_adw Hepatitis b virus subtype adw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G33 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Hepatitis b virus subtype adw]] | [[Category: Hepatitis b virus subtype adw]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bourne, C | [[Category: Bourne, C R.]] | ||
[[Category: Zlotnick, A.]] | [[Category: Zlotnick, A.]] | ||
[[Category: capsid]] | [[Category: capsid]] | ||
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[[Category: virus]] | [[Category: virus]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:27:48 2008'' | ||
Revision as of 18:27, 21 February 2008
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Human Hepatitis B Virus T=4 capsid, strain adyw
OverviewOverview
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-dihydropyrimidin e-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.
About this StructureAbout this Structure
2G33 is a Single protein structure of sequence from Hepatitis b virus subtype adw. Full crystallographic information is available from OCA.
ReferenceReference
Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1., Bourne CR, Finn MG, Zlotnick A, J Virol. 2006 Nov;80(22):11055-61. Epub 2006 Aug 30. PMID:16943288
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