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- PDB-7lbg: CryoEM structure of the HCMV Trimer gHgLgO in complex with human ... -

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Basic information

Entry
Database: PDB / ID: 7lbg
TitleCryoEM structure of the HCMV Trimer gHgLgO in complex with human Transforming growth factor beta receptor type 3 and neutralizing fabs 13H11 and MSL-109
Components
  • (Envelope glycoprotein ...) x 3
  • Fab 13H11 heavy chain
  • Fab 13H11 light chain
  • Fab MSL-109 heavy chain
  • Fab MSL-109 light chain
  • Transforming growth factor beta receptor type 3
KeywordsVIRAL PROTEIN/Immune System / virus / receptor / complex / neutralizing antibody / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


response to luteinizing hormone / transforming growth factor beta receptor complex assembly / epicardium-derived cardiac fibroblast cell development / transforming growth factor beta receptor activity, type III / inhibin-betaglycan-ActRII complex / TGFBR3 regulates activin signaling / response to follicle-stimulating hormone / muscular septum morphogenesis / definitive erythrocyte differentiation / TGFBR3 regulates FGF2 signaling ...response to luteinizing hormone / transforming growth factor beta receptor complex assembly / epicardium-derived cardiac fibroblast cell development / transforming growth factor beta receptor activity, type III / inhibin-betaglycan-ActRII complex / TGFBR3 regulates activin signaling / response to follicle-stimulating hormone / muscular septum morphogenesis / definitive erythrocyte differentiation / TGFBR3 regulates FGF2 signaling / BMP binding / vasculogenesis involved in coronary vascular morphogenesis / transforming growth factor beta receptor activity / TGFBR3 PTM regulation / regulation of transforming growth factor beta receptor signaling pathway / secondary palate development / ventricular compact myocardium morphogenesis / TGFBR3 regulates TGF-beta signaling / cardiac epithelial to mesenchymal transition / transforming growth factor beta receptor binding / type II transforming growth factor beta receptor binding / activin binding / FGFR1b ligand binding and activation / heart trabecula morphogenesis / FGFR1c ligand binding and activation / Signaling by BMP / Signaling by Activin / glycosaminoglycan binding / heart trabecula formation / definitive hemopoiesis / transforming growth factor beta binding / TGFBR3 expression / negative regulation of extracellular matrix assembly / positive regulation of cell migration involved in sprouting angiogenesis / ventricular cardiac muscle tissue morphogenesis / ventricular septum morphogenesis / negative regulation of SMAD protein signal transduction / SMAD binding / positive regulation of transforming growth factor beta receptor signaling pathway / fibroblast growth factor binding / TGF-beta receptor signaling activates SMADs / outflow tract morphogenesis / positive regulation of SMAD protein signal transduction / epithelial to mesenchymal transition / animal organ regeneration / cardiac muscle cell proliferation / BMP signaling pathway / heart morphogenesis / coreceptor activity / positive regulation of cardiac muscle cell proliferation / response to prostaglandin E / negative regulation of canonical NF-kappaB signal transduction / transforming growth factor beta receptor signaling pathway / negative regulation of cell migration / host cell endosome membrane / HCMV Late Events / PDZ domain binding / negative regulation of transforming growth factor beta receptor signaling pathway / liver development / HCMV Early Events / negative regulation of epithelial cell proliferation / transmembrane signaling receptor activity / cell migration / heparin binding / host cell Golgi apparatus / basolateral plasma membrane / entry receptor-mediated virion attachment to host cell / response to hypoxia / receptor complex / intracellular signal transduction / immune response / fusion of virus membrane with host plasma membrane / external side of plasma membrane / viral envelope / positive regulation of gene expression / symbiont entry into host cell / host cell plasma membrane / virion membrane / cell surface / extracellular space / extracellular exosome / extracellular region / plasma membrane / cytosol
Similarity search - Function
Herpesvirus UL74, glycoprotein / Herpes UL74 glycoproteins / Cytomegalovirus glycoprotein L / Cytomegalovirus glycoprotein L / Betaherpesvirus glycoprotein L (gL) domain profile. / 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 ...Herpesvirus UL74, glycoprotein / Herpes UL74 glycoproteins / Cytomegalovirus glycoprotein L / Cytomegalovirus glycoprotein L / Betaherpesvirus glycoprotein L (gL) domain profile. / 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 / : / Zona pellucida domain, conserved site / ZP domain signature. / : / : / ZP-N domain / Zona pellucida, ZP-C domain / ZP-C domain / Zona pellucida (ZP) domain / ZP domain profile. / Zona pellucida domain
Similarity search - Domain/homology
Envelope glycoprotein L / Transforming growth factor beta receptor type 3 / Envelope glycoprotein H / Envelope glycoprotein O
Similarity search - Component
Biological speciesHuman cytomegalovirus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsKschonsak, M. / Rouge, L. / Arthur, C.P. / Hoangdung, H. / Patel, N. / Kim, I. / Johnson, M. / Kraft, E. / Rohou, A.L. / Gill, A. ...Kschonsak, M. / Rouge, L. / Arthur, C.P. / Hoangdung, H. / Patel, N. / Kim, I. / Johnson, M. / Kraft, E. / Rohou, A.L. / Gill, A. / Martinez-Martin, N. / Payandeh, J. / Ciferri, C.
CitationJournal: Cell / Year: 2021
Title: Structures of HCMV Trimer reveal the basis for receptor recognition and cell entry.
Authors: Marc Kschonsak / Lionel Rougé / Christopher P Arthur / Ho Hoangdung / Nidhi Patel / Ingrid Kim / Matthew C Johnson / Edward Kraft / Alexis L Rohou / Avinash Gill / Nadia Martinez-Martin / ...Authors: Marc Kschonsak / Lionel Rougé / Christopher P Arthur / Ho Hoangdung / Nidhi Patel / Ingrid Kim / Matthew C Johnson / Edward Kraft / Alexis L Rohou / Avinash Gill / Nadia Martinez-Martin / Jian Payandeh / Claudio Ciferri /
Abstract: Human cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind ...Human cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind to platelet-derived growth factor receptor alpha (PDGFRα) and transforming growth factor beta receptor 3 (TGFβR3) to gain entry into multiple cell types. This complex is targeted by potent neutralizing antibodies and represents an important candidate for therapeutics against HCMV. Here, we determine three cryogenic electron microscopy (cryo-EM) structures of the trimer and the details of its interactions with four binding partners: the receptor proteins PDGFRα and TGFβR3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFRα and TGFβR3 is mutually exclusive, suggesting that they function as independent entry receptors. In addition, Trimer-PDGFRα interaction has an inhibitory effect on PDGFRα signaling. Our results provide a framework for understanding HCMV receptor engagement, neutralization, and the development of anti-viral strategies against HCMV.
History
DepositionJan 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 17, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Envelope glycoprotein H
B: Envelope glycoprotein L
C: Envelope glycoprotein O
D: Transforming growth factor beta receptor type 3
E: Fab 13H11 light chain
F: Fab 13H11 heavy chain
G: Fab MSL-109 light chain
H: Fab MSL-109 heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)377,52227
Polymers372,1028
Non-polymers5,42019
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Eluted as monodispersed peak
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Envelope glycoprotein ... , 3 types, 3 molecules ABC

#1: Protein Envelope glycoprotein H / gH


Mass: 87311.273 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus (strain Merlin) / Strain: Merlin / Gene: gH, UL75 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: Q6SW67
#2: Protein Envelope glycoprotein L / gL


Mass: 30846.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus (strain Merlin) / Strain: Merlin / Gene: gL, UL115 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: F5HCH8
#3: Protein Envelope glycoprotein O / UL74 / UL74 protein


Mass: 58298.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Gene: UL74 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: Q8BCU3

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Protein , 1 types, 1 molecules D

#4: Protein Transforming growth factor beta receptor type 3 / TGFR-3 / Betaglycan / Transforming growth factor beta receptor III / TGF-beta receptor type III


Mass: 87362.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q03167

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Antibody , 4 types, 4 molecules EFGH

#5: Antibody Fab 13H11 light chain


Mass: 25780.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#6: Antibody Fab 13H11 heavy chain


Mass: 26600.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#7: Antibody Fab MSL-109 light chain


Mass: 28355.809 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#8: Antibody Fab MSL-109 heavy chain


Mass: 27547.818 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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Sugars , 3 types, 19 molecules

#9: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][<C7N1O4>]{[(1+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#10: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-3DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1_f3-g1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#11: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1HCMV Trimer gHgLgO bound to human receptor TGFbR3 and neutralizing fabs 13H11 and MSL-109COMPLEX#1-#80MULTIPLE SOURCES
2HCMV Trimer gHgLgOCOMPLEX#1-#31RECOMBINANT
3neutralizing fabs 13H11 and MSL-109COMPLEX#4-#81RECOMBINANT
Molecular weightValue: 0.36 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
23Homo sapiens (human)9606
32Human cytomegalovirus HHV-510359
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
23Escherichia coli (E. coli)562
32Homo sapiens (human)9606
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
10.3 Msodium chlorideNaCl1
20.025 MHEPES1
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: blot for 3.5 seconds before plunging

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 10 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 19993 / Details: Images were collected in 50 frames every 0.2 s
Image scansMovie frames/image: 50

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Processing

EM software
IDNameVersionCategoryDetails
1Gautomatch0.56particle selection
2SerialEM3.7.11image acquisition
4CTFFINDCTF correction4.1.13
7UCSF Chimera1.13.1model fitting
8Coot0.8.9model fitting
10PHENIX1.19model refinement
11ISOLDE1.1.0model refinement
12cisTEM1.02initial Euler assignment
13cisTEM1.02final Euler assignment
14RELION3.1classification
15cisTEM1.023D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2780519
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2737199
Details: Used a score threshold of 0.25 for final 3D reconstruction. Map used for model refinements is a composite map after combining 2 focussed maps with PHENIX
Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL

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