6ECS
Crystal structure of WHV core protein mutant Y132A dimer
Summary for 6ECS
| Entry DOI | 10.2210/pdb6ecs/pdb |
| Descriptor | External core antigen (1 entity in total) |
| Functional Keywords | whv, core protein dimer, viral protein |
| Biological source | Woodchuck hepatitis B virus (WHV) |
| Total number of polymer chains | 4 |
| Total formula weight | 68137.48 |
| Authors | Zhao, Z.,Gonzalez-Gutierrez, G.,Zlotnick, A. (deposition date: 2018-08-08, release date: 2019-05-01, Last modification date: 2024-11-20) |
| Primary citation | Zhao, Z.,Wang, J.C.,Gonzalez-Gutierrez, G.,Venkatakrishnan, B.,Asor, R.,Khaykelson, D.,Raviv, U.,Zlotnick, A. Structural Differences between the Woodchuck Hepatitis Virus Core Protein in the Dimer and Capsid States Are Consistent with Entropic and Conformational Regulation of Assembly. J.Virol., 93:-, 2019 Cited by PubMed Abstract: Hepadnaviruses are hepatotropic enveloped DNA viruses with an icosahedral capsid. Hepatitis B virus (HBV) causes chronic infection in an estimated 240 million people; woodchuck hepatitis virus (WHV), an HBV homologue, has been an important model system for drug development. The dimeric capsid protein (Cp) has multiple functions during the viral life cycle and thus has become an important target for a new generation of antivirals. Purified HBV and WHV Cp spontaneously assemble into 120-dimer capsids. Though they have 65% identity, WHV Cp has error-prone assembly with stronger protein-protein association. We have taken advantage of the differences in assemblies to investigate the basis of assembly regulation. We determined the structures of the WHV capsid to 4.5-Å resolution by cryo-electron microscopy (cryo-EM) and of the WHV Cp dimer to 2.9-Å resolution by crystallography and examined the biophysical properties of the dimer. We found, in dimer, that the subdomain that makes protein-protein interactions is partially disordered and rotated 21° from its position in capsid. This subdomain is susceptible to proteolysis, consistent with local disorder. WHV assembly shows similar susceptibility to HBV antiviral molecules, suggesting that HBV assembly follows similar transitions. These data show that there is an entropic cost for assembly that is compensated for by the energetic gain of burying hydrophobic interprotein contacts. We propose a series of stages in assembly that incorporate a disorder-to-order transition and structural shifts. We suggest that a cascade of structural changes may be a common mechanism for regulating high-fidelity capsid assembly in HBV and other viruses. Virus capsids assemble spontaneously with surprisingly high fidelity. This requires strict geometry and a narrow range of association energies for these protein-protein interactions. It was hypothesized that requiring subunits to undergo a conformational change to become assembly active could regulate assembly by creating an energetic barrier and attenuating association. We found that woodchuck hepatitis virus capsid protein undergoes structural transitions between its dimeric and its 120-dimer capsid states. It is likely that the closely related hepatitis B virus capsid protein undergoes similar structural changes, which has implications for drug design. Regulation of assembly by structural transition may be a common mechanism for many viruses. PubMed: 31043524DOI: 10.1128/JVI.00141-19 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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