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- PDB-7kbb: Cryo-EM structure of the HCMV pentamer bound by Fabs 2-18 and 8I21 -

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Basic information

Entry
Database: PDB / ID: 7kbb
TitleCryo-EM structure of the HCMV pentamer bound by Fabs 2-18 and 8I21
Components
  • 2-18 Fab Heavy Chain
  • 2-18 Fab Light Chain
  • 8I21 Fab Heavy Chain
  • 8I21 Fab Light Chain
  • Envelope glycoprotein UL130
  • Envelope protein UL128
  • UL131A
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HCMV pentamer / Fab / complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homologyHerpesvirus UL130, cytomegalovirus / HCMV glycoprotein pUL130 / viral envelope / Envelope glycoprotein UL130 / UL128 / UL131A
Function and homology information
Biological speciesHomo sapiens (human)
Human cytomegalovirus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.02 Å
AuthorsWrapp, D. / McLellan, J.S.
CitationJournal: Sci Adv / Year: 2022
Title: Structural basis for HCMV Pentamer recognition by neuropilin 2 and neutralizing antibodies.
Authors: Daniel Wrapp / Xiaohua Ye / Zhiqiang Ku / Hang Su / Harrison G Jones / Nianshuang Wang / Akaash K Mishra / Daniel C Freed / Fengsheng Li / Aimin Tang / Leike Li / Dabbu Kumar Jaijyan / Hua ...Authors: Daniel Wrapp / Xiaohua Ye / Zhiqiang Ku / Hang Su / Harrison G Jones / Nianshuang Wang / Akaash K Mishra / Daniel C Freed / Fengsheng Li / Aimin Tang / Leike Li / Dabbu Kumar Jaijyan / Hua Zhu / Dai Wang / Tong-Ming Fu / Ningyan Zhang / Zhiqiang An / Jason S McLellan /
Abstract: Human cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into ...Human cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into epithelial, endothelial, and myeloid cells by interacting with the cell surface receptor neuropilin 2 (NRP2). Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here, we describe the cryo-EM structure of NRP2 bound to Pentamer. The high-affinity interaction between these proteins is calcium dependent and differs from the canonical carboxyl-terminal arginine (CendR) binding that NRP2 typically uses. We also determine the structures of four neutralizing human antibodies bound to the HCMV Pentamer to define susceptible epitopes. Two of these antibodies compete with NRP2 binding, but the two most potent antibodies recognize a previously unidentified epitope that does not overlap the NRP2-binding site. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization.
History
DepositionOct 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: 2-18 Fab Heavy Chain
B: 2-18 Fab Light Chain
C: Envelope protein UL128
D: Envelope glycoprotein UL130
E: UL131A
H: 8I21 Fab Heavy Chain
L: 8I21 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)149,1617
Polymers149,1617
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area16650 Å2
ΔGint-95 kcal/mol
Surface area36900 Å2

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Components

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Protein , 3 types, 3 molecules CDE

#3: Protein Envelope protein UL128 / UL128


Mass: 16684.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Gene: UL128 / Production host: Homo sapiens (human) / References: UniProt: C8BLJ3
#4: Protein Envelope glycoprotein UL130 / ORFL272C_UL130 / UL130 protein


Mass: 21761.678 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Gene: UL130 / Production host: Homo sapiens (human) / References: UniProt: A0A0G2TB82
#5: Protein UL131A


Mass: 13005.457 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Production host: Homo sapiens (human) / References: UniProt: Q38M21

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Antibody , 4 types, 4 molecules ABHL

#1: Antibody 2-18 Fab Heavy Chain


Mass: 25640.506 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody 2-18 Fab Light Chain


Mass: 23414.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#6: Antibody 8I21 Fab Heavy Chain


Mass: 25196.340 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#7: Antibody 8I21 Fab Light Chain


Mass: 23459.006 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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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

Component
IDNameTypeEntity IDParent-IDSource
1HCMV pentamer bound by antibodies 2-18 and 8I21COMPLEXall0MULTIPLE SOURCES
2HCMV pentamer (refinement focused on three of the subunits)COMPLEX#3-#51RECOMBINANT
3Fab 2-18COMPLEX#1-#21RECOMBINANT
4Fab 8I21COMPLEX#6-#71RECOMBINANT
Molecular weightValue: 0.28 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Human betaherpesvirus 510359
33Homo sapiens (human)9606
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
12 mMTrisC4H11NO31
2200 mMsodium chlorideNaCl1
30.2 %sodium azideNaN31
40.01 %amphipol A8-35(C6.2H10.3O1.35N0.65Na0.35)721
SpecimenConc.: 0.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / C2 aperture diameter: 100 µm
Image recordingElectron dose: 36 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Classification: refinement
EM software
IDNameCategory
1Warpparticle selection
4cryoSPARCCTF correction
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.02 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 249802 / Symmetry type: POINT
RefinementCross valid method: THROUGHOUT
Displacement parametersBiso max: 102.73 Å2 / Biso mean: 57.7257 Å2 / Biso min: 30 Å2

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