6B43

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

  • Classification: VIRUS
  • Organism(s): Human gammaherpesvirus 8
  • Mutation(s): No 

  • Deposited: 2017-09-25 Released: 2017-11-08 
  • Deposition Author(s): Dai, X.H., Gong, D.Y., Sun, R., Zhou, Z.H.
  • Funding Organization(s): National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR), National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID), National Institutes of Health/National Cancer Institute (NIH/NCI), National Institutes of Health/Office of the Director, National Science Foundation (NSF, United States)

Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.6 of the entry. See complete history


Literature

Structure and mutagenesis reveal essential capsid protein interactions for KSHV replication.

Dai, X.Gong, D.Lim, H.Jih, J.Wu, T.T.Sun, R.Zhou, Z.H.

(2018) Nature 553: 521-525

  • DOI: https://doi.org/10.1038/nature25438
  • Primary Citation of Related Structures:  
    6B43

  • 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.


  • Organizational Affiliation

    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, California 90095, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Major capsid protein
A,
B,
C,
D,
E,
EA [auth 4],
F,
M,
N,
O,
S,
T,
U,
V,
W,
X
1,376Human gammaherpesvirus 8Mutation(s): 0 
UniProt
Find proteins for D0UZN7 (Human herpesvirus 8)
Explore D0UZN7 
Go to UniProtKB:  D0UZN7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupD0UZN7
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Small capsomere-interacting protein170Human gammaherpesvirus 8Mutation(s): 0 
UniProt
Find proteins for Q76RF4 (Human herpesvirus 8)
Explore Q76RF4 
Go to UniProtKB:  Q76RF4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ76RF4
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Triplex capsid protein 1FA [auth 5],
IA [auth 8],
LA [auth b],
OA [auth e],
RA [auth h]
331Human gammaherpesvirus 8Mutation(s): 0 
UniProt
Find proteins for Q76RF6 (Human herpesvirus 8)
Explore Q76RF6 
Go to UniProtKB:  Q76RF6
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UniProt GroupQ76RF6
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Triplex capsid protein 2305Human gammaherpesvirus 8Mutation(s): 0 
UniProt
Find proteins for C7E5A9 (Human herpesvirus 8)
Explore C7E5A9 
Go to UniProtKB:  C7E5A9
Entity Groups  
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UniProt GroupC7E5A9
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
MODEL REFINEMENTPHENIX

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)United StatesDE025567
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM071940
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI094386
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA091791
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA177322
National Institutes of Health/Office of the DirectorUnited States1S10OD018111
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States1U24GM116792
National Science Foundation (NSF, United States)United StatesDBI-1338135

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-08
    Type: Initial release
  • Version 1.1: 2017-12-06
    Changes: Author supporting evidence, Other
  • Version 1.2: 2018-01-31
    Changes: Database references
  • Version 1.3: 2018-02-07
    Changes: Database references
  • Version 1.4: 2018-04-11
    Changes: Advisory, Data collection
  • Version 1.5: 2019-11-27
    Changes: Author supporting evidence
  • Version 1.6: 2019-12-18
    Changes: Other