Current projects

3)  In situ structures of three components essential to human cytomegalovirus pathogenesis: genome-packaging machinery, capsid-associated tegument and prefusion glycoprotein complexes               Project number: 5R01DE028583-05 

Human cytomegalovirus (HCMV) is a leading viral cause of birth defects and can be life-threatening to immune-compromised individuals. As a member of the Betaherpesvirinae subfamily of the Herpesviridae and the most structurally and genetically complex herpesvirus, HCMV is one of the largest of all viruses and presents a major challenge to structure determination. HCMV is composed of a glycoprotein-containing envelope, a tegument layer, and a bacteriophage-like icosahedral capsid enclosing a genome of a single dsDNA molecule. 

Distinctive from members of the α- and γ-herpesvirus subfamilies are two processes central to HCMV infection: 1) its large genome needs to be packaged through a portal complex and then stabilized by a unique tegument protein pp150; 2) the process of cell fusion by gB involves a unique pentameric glycoprotein complex gH/gL/UL128/UL130/UL131. These processes thus can be targeted for structure-guided design for novel vaccines and anti-virals against HCMV infections. 

Our group previously obtained the first three-dimensional structure of the HCMV capsid at 18 Å resolution in 1999, which was followed by progressive improvement in resolution, culminating at the recent 3.9 Å resolution structure reported in Science. We hypothesize that our state-of-the-art technologies in electron-counting cryoEM, symmetry relaxation and local refinement methods, and HCMV BAC technologies together would now allow us to: 
    (1) obtain in situ structure of the portal of DNA genome packaging and ejection machinery at near-atomic resolution and identify residues critical to capsid assembly and stabilization; 
    (2) determine the in situ structure of pp150 at about 2 Å resolution and identify the chemical bonds between capsid and capsid-interacting pp150 residues, particularly the cys tetrad conserved among primate cytomegaloviruses; 
    (3) obtain atomic structures of purified pentameric glycoprotein complex in complex with three neutralizing monoclonal antibodies, as well as their in situ pre-fusion glycoprotein structures on viral envelope by cryo electron tomography for comparison. 

The expected results should inform efforts in designing inhibitors and vaccines against HCMV infections.

Select publications:

Structure of human cytomegalovirus virion reveals host tRNA binding to capsid-associated tegument protein pp150.
Liu, Y.-T., Strugatsky, D., Liu, W. & Zhou, Z. H. (2021). Nature Communications
Different functional states of fusion protein gB revealed on human cytomegalovirus by cryo electron tomography with Volta phase plate.
Si, Z., Zhang, J., Shivakoti, S., Atanasov, I., Tao, C.-L., Hui, W. H., Zhou, K., Yu, X., Li, W., Luo, M., Bi, G.-Q. & Zhou, Z. H. (2018). PLoS Pathogens
Atomic structure of the human cytomegalovirus capsid with its securing tegument layer of pp150.
Yu, X., Jih, J., Jiang, J. & Zhou, Z. H. (2017). Science

Research & Facilities 

Zhou Lab
California Nanosystems Institute (CNSI)
University of California Los Angeles (UCLA)
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