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- PDB-6wxl: Cryo-EM structure of the VRC315 clinical trial, vaccine-elicited,... -

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Basic information

Entry
Database: PDB / ID: 6wxl
TitleCryo-EM structure of the VRC315 clinical trial, vaccine-elicited, human antibody 1D12 in complex with an H7 SH13 HA trimer
Components
  • 1D12 Light chain
  • 1D21 Heavy chain
  • Hemagglutinin HA1 chain
  • Hemagglutinin HA2 chain
KeywordsIMMUNE SYSTEM / VRC / VRC315 / Group 2 / Fab
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / membrane => GO:0016020 / host cell surface receptor binding / apical plasma membrane / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane
Similarity search - Function
Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein
Similarity search - Domain/homology
Biological speciesInfluenza A virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsGorman, J. / Kwong, P.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
CitationJournal: Structure / Year: 2022
Title: Structure of an influenza group 2-neutralizing antibody targeting the hemagglutinin stem supersite.
Authors: Crystal Sao-Fong Cheung / Jason Gorman / Sarah F Andrews / Reda Rawi / Mateo Reveiz / Chen-Hsiang Shen / Yiran Wang / Darcy R Harris / Alexandra F Nazzari / Adam S Olia / Julie Raab / I-Ting ...Authors: Crystal Sao-Fong Cheung / Jason Gorman / Sarah F Andrews / Reda Rawi / Mateo Reveiz / Chen-Hsiang Shen / Yiran Wang / Darcy R Harris / Alexandra F Nazzari / Adam S Olia / Julie Raab / I-Ting Teng / Raffaello Verardi / Shuishu Wang / Yongping Yang / Gwo-Yu Chuang / Adrian B McDermott / Tongqing Zhou / Peter D Kwong /
Abstract: Several influenza antibodies with broad group 2 neutralization have recently been isolated. Here, we analyze the structure, class, and binding of one of these antibodies from an H7N9 vaccine trial, ...Several influenza antibodies with broad group 2 neutralization have recently been isolated. Here, we analyze the structure, class, and binding of one of these antibodies from an H7N9 vaccine trial, 315-19-1D12. The cryo-EM structure of 315-19-1D12 Fab in complex with the hemagglutinin (HA) trimer revealed the antibody to recognize the helix A region of the HA stem, at the supersite of vulnerability recognized by group 1-specific and by cross-group-neutralizing antibodies. 315-19-1D12 was derived from HV1-2 and KV2-28 genes and appeared to form a new antibody class. Bioinformatic analysis indicated its group 2 neutralization specificity to be a consequence of four key residue positions. We specifically tested the impact of the group 1-specific N33 glycan, which decreased but did not abolish group 2 binding of 315-19-1D12. Overall, this study highlights the recognition of a broad group 2-neutralizing antibody, revealing unexpected diversity in neutralization specificity for antibodies that recognize the HA stem supersite.
History
DepositionMay 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 9, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 22, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-21961
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Hemagglutinin HA1 chain
B: Hemagglutinin HA2 chain
L: 1D12 Light chain
H: 1D21 Heavy chain
D: Hemagglutinin HA2 chain
E: 1D12 Light chain
F: 1D21 Heavy chain
I: Hemagglutinin HA2 chain
J: 1D12 Light chain
K: 1D21 Heavy chain
C: Hemagglutinin HA1 chain
G: Hemagglutinin HA1 chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)329,85421
Polymers327,86312
Non-polymers1,9919
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Hemagglutinin HA1 chain


Mass: 35039.473 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (A/Shanghai/JS01/2013(H7N9))
Strain: A/Shanghai/JS01/2013(H7N9) / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: A0A067Y6L0
#2: Protein Hemagglutinin HA2 chain


Mass: 25234.352 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (A/Shanghai/JS01/2013(H7N9))
Strain: A/Shanghai/JS01/2013(H7N9) / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: A0A067Y6L0
#3: Antibody 1D12 Light chain


Mass: 23971.762 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody 1D21 Heavy chain


Mass: 25042.229 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 9
Source method: isolated from a genetically manipulated source
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
Has ligand of interestN

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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
11D12 in complex with an H7 SH13 HA trimerCOMPLEX#1-#40RECOMBINANT
2H7 SH13 HA trimerCOMPLEX#1-#21RECOMBINANT
31D12 FabCOMPLEX#3-#41RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Influenza A virus11320
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Buffer solutionpH: 7.4
Buffer componentFormula: PBS
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Cryo-EM structure of the VRC315 clinical trial, vaccine-elicited, human antibody 1D12 in complex with an H7 SH13 HA trimer
Specimen supportGrid material: COPPER / Grid type: C-flat-1.2/1.3 4C
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 293 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 FIELDBright-field microscopy / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 49.9 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1878
Image scansMovie frames/image: 50

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategory
2Leginonimage acquisition
4CTFFIND4CTF correction
11cryoSPARC2.12classification
12cryoSPARC2.123D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142628 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-ID
14HK0

4hk0

1
26IDD

6idd

1
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00517352
ELECTRON MICROSCOPYf_angle_d0.69723457
ELECTRON MICROSCOPYf_dihedral_angle_d13.80610353
ELECTRON MICROSCOPYf_chiral_restr0.0492556
ELECTRON MICROSCOPYf_plane_restr0.0063069

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