6B43

CryoEM structure and atomic model of the Kaposi's sarcoma-associated herpesvirus capsid

This is a non-PDB format compatible entry.

Replaces:  3J9A

Summary for 6B43

• Entry DOI: 10.2210/pdb6b43/pdb
• EMDB information: 7047
• Descriptor: Major capsid protein, Small capsomere-interacting protein, Triplex capsid protein 1, ... (4 entities in total)
• Functional Keywords: human herpesvirus 8, human tumor virus, dsdna virus capsid assembly, hk97-like fold, virus
• Biological source: Human herpesvirus 8 (HHV-8); More
• Total number of polymer chains: 46
• Total formula weight: 3260813.30

Authors

Dai, X.H.,Gong, D.Y.,Sun, R.,Zhou, Z.H. (deposition date: 2017-09-25, release date: 2017-11-08, Last modification date: 2024-11-20)

Primary citation

Dai, X.,Gong, D.,Lim, H.,Jih, J.,Wu, T.T.,Sun, R.,Zhou, Z.H.
Structure and mutagenesis reveal essential capsid protein interactions for KSHV replication.
Nature, 553:521-525, 2018

PubMed Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, a cancer that commonly affects patients with AIDS and which is endemic in sub-Saharan Africa. The KSHV capsid is highly pressurized by its double-stranded DNA genome, as are the capsids of the eight other human herpesviruses. Capsid assembly and genome packaging of herpesviruses are prone to interruption and can therefore be targeted for the structure-guided development of antiviral agents. However, herpesvirus capsids-comprising nearly 3,000 proteins and over 1,300 Å in diameter-present a formidable challenge to atomic structure determination and functional mapping of molecular interactions. Here we report a 4.2 Å resolution structure of the KSHV capsid, determined by electron-counting cryo-electron microscopy, and its atomic model, which contains 46 unique conformers of the major capsid protein (MCP), the smallest capsid protein (SCP) and the triplex proteins Tri1 and Tri2. Our structure and mutagenesis results reveal a groove in the upper domain of the MCP that contains hydrophobic residues that interact with the SCP, which in turn crosslinks with neighbouring MCPs in the same hexon to stabilize the capsid. Multiple levels of MCP-MCP interaction-including six sets of stacked hairpins lining the hexon channel, disulfide bonds across channel and buttress domains in neighbouring MCPs, and an interaction network forged by the N-lasso domain and secured by the dimerization domain-define a robust capsid that is resistant to the pressure exerted by the enclosed genome. The triplexes, each composed of two Tri2 molecules and a Tri1 molecule, anchor to the capsid floor via a Tri1 N-anchor to plug holes in the MCP network and rivet the capsid floor. These essential roles of the MCP N-lasso and Tri1 N-anchor are verified by serial-truncation mutageneses. Our proof-of-concept demonstration of the use of polypeptides that mimic the smallest capsid protein to inhibit KSHV lytic replication highlights the potential for exploiting the interaction hotspots revealed in our atomic structure to develop antiviral agents.

PubMed: 29342139
DOI: 10.1038/nature25438

Experimental method

ELECTRON MICROSCOPY (4.2 Å)