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- PDB-9z3q: Cryo-EM structure of KSHV glycoprotein gHgL in complex with MLKH3... -

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Basic information

Entry
Database: PDB / ID: 9z3q
TitleCryo-EM structure of KSHV glycoprotein gHgL in complex with MLKH3 and MLKH10 FABs
Components
  • (Envelope glycoprotein ...) x 2
  • MLKH10 Heavy chain FV
  • MLKH10 Light chain FV
  • MLKH3 Heavy chain FV
  • MLKH3 Light chain FV
KeywordsIMMUNE SYSTEM / KSHV / glycoprotein / Antibody
Function / homology
Function and homology information


host cell endosome membrane / host cell Golgi apparatus / fusion of virus membrane with host plasma membrane / viral envelope / symbiont entry into host cell / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Herpesvirus glycoprotein L, rhadinovirus-type / Herpesvirus glycoprotein L, rhadinovirus-type superfamily / Viral glycoprotein L / Envelope glycoprotein L / Herpesvirus glycoprotein H main domain / Herpesvirus glycoprotein H / Herpesvirus glycoprotein H, C-terminal / Herpesvirus glycoprotein H, C-terminal domain superfamily / Herpesvirus glycoprotein H C-terminal domain
Similarity search - Domain/homology
Envelope glycoprotein H / Envelope glycoprotein L
Similarity search - Component
Biological speciesMus musculus (house mouse)
Human gammaherpesvirus 8
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.51 Å
AuthorsLang, K. / Aldridge, N. / Pancera, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)U01CA295050 United States
CitationJournal: PLoS Pathog / Year: 2026
Title: Monoclonal neutralizing antibodies elicited by infection with Kaposi sarcoma-associated herpesvirus reveal critical sites of vulnerability on gH/gL.
Authors: Yu-Hsin Wan / Sara Pernikoff / Nicholas T Aldridge / Kevin Lang / Holly M Dudley / Samuel C Scharffenberger / Gargi Kher / Warren Phipps / Marie Pancera / Jim Boonyaratanakornkit / Andrew T McGuire /
Abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. A vaccine that prevents KSHV infection or ...Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. A vaccine that prevents KSHV infection or serves in the treatment of KSHV-related diseases represents a critical unmet need, however, the types of immune responses a vaccine should elicit have not been well defined. The gH/gL glycoprotein complex is an important target of KSHV-neutralizing antibodies, but the epitope specificities targeted by these antibodies remain unknown. Here, we isolated 12 gH/gL-specific monoclonal antibodies (mAbs) from KSHV-infected donors and performed structure/function analyses. These mAbs bind recombinant gH/gL with nanomolar affinities and epitope binning analyses revealed that the mAbs bind to 5 epitope clusters on gH/gL. Seven mAbs were able to neutralize KSHV infection of epithelial cell lines. Two potent neutralizing mAbs mapped to the EphA2 binding site as determined by inhibition of the receptor-ligand interaction and negative stain electron microscopy (nsEM) of the mAb/gH/gL complex. The epitopes of other neutralizing mAbs targeting novel sites of vulnerability were determined by a combination of cryogenic electron microscopy and nsEM. Together, these mAbs help to define the relevant epitope targets for KSHV vaccine design, have utility in understanding the role of antibodies in preventing KSHV infection, enable the development of immunotherapy approaches, and provide valuable tools to understand the molecular details of the KSHV entry process.
History
DepositionNov 7, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 10, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Jan 21, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MLKH10 Light chain FV
B: MLKH10 Heavy chain FV
C: MLKH3 Light chain FV
D: MLKH3 Heavy chain FV
E: Envelope glycoprotein H
F: Envelope glycoprotein L


Theoretical massNumber of molelcules
Total (without water)149,9336
Polymers149,9336
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Envelope glycoprotein ... , 2 types, 2 molecules EF

#5: Protein Envelope glycoprotein H / gH


Mass: 80917.531 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human gammaherpesvirus 8 / Strain: gk18 / Gene: gH, ORF22 / Plasmid: pTT3 / Cell (production host): Epithelial-like / Cell line (production host): HEK293S / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / Tissue (production host): KIDNEY / References: UniProt: F5HAK9
#6: Protein Envelope glycoprotein L / gL


Mass: 18815.754 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human gammaherpesvirus 8 / Strain: gk18 / Gene: gL, 47 / Plasmid: pTT3 / Cell (production host): Epithelial-like / Cell line (production host): HEK293S / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / Tissue (production host): KIDNEY / References: UniProt: F5HDB7

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Antibody , 4 types, 4 molecules ABCD

#1: Antibody MLKH10 Light chain FV


Mass: 12427.777 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pTT3 / Cell (production host): Epithelial-like / Cell line (production host): HEK293S / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / Tissue (production host): KIDNEY
#2: Antibody MLKH10 Heavy chain FV


Mass: 13144.362 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pTT3 / Cell (production host): Epithelial-like / Cell line (production host): HEK293S / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / Tissue (production host): KIDNEY
#3: Antibody MLKH3 Light chain FV


Mass: 11538.785 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pTT3 / Cell (production host): Epithelial-like / Cell line (production host): HEK293S / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / Tissue (production host): KIDNEY
#4: Antibody MLKH3 Heavy chain FV


Mass: 13088.487 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pTT3 / Cell (production host): Epithelial-like / Cell line (production host): HEK293S / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / Tissue (production host): KIDNEY

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: KSHV glycoprotein heterodimer gHgL 1:1 MLKH3 and MLKH10 FABs
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 0.184 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Epithelial-like / Plasmid: pTT3
Buffer solutionpH: 7 / Details: 1x TBS
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: OTHER
Image recordingAverage exposure time: 6 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 9372

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.7.1particle selection
7UCSF ChimeraX1.9model fitting
12cryoSPARC4.7.13D reconstruction
13PHENIX2.0_5793model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 19982448
3D reconstructionResolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75257 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDPdb chain-IDChain-IDSource nameTypeAccession codeInitial refinement model-ID
1AAlphaFoldin silico model
2BAlphaFoldin silico model
3CAlphaFoldin silico model
4DAlphaFoldin silico model
57CZF

7czf

EEPDBexperimental model7CZF2
67CZF

7czf

GGPDBexperimental model7CZF2
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 103.19 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00359652
ELECTRON MICROSCOPYf_angle_d0.783613126
ELECTRON MICROSCOPYf_chiral_restr0.04631490
ELECTRON MICROSCOPYf_plane_restr0.00651672
ELECTRON MICROSCOPYf_dihedral_angle_d5.53981337

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