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- PDB-7mem: CryoEM structure of monoclonal Fab 045-09 2B05 binding the latera... -

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Basic information

Entry
Database: PDB / ID: 7mem
TitleCryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of influenza virus H1 HA
Components
  • (Hemagglutinin ...) x 2
  • Heavy chain of monoclonal antibody 045-09 2B05
  • Light chain of monoclonal antibody 045-09 2B05
KeywordsViral protein/IMMUNE SYSTEM / Hemagglutinin / monoclonal antibody / influenza virus / IMMUNE SYSTEM / Viral protein-IMMUNE SYSTEM complex
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / host cell surface receptor binding / 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 / metal ion binding / membrane
Similarity search - Function
Hemagglutinin Ectodomain; Chain B - #10 / Hemagglutinin Ectodomain; Chain B / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / Immunoglobulins / Alpha-Beta Complex / Immunoglobulin-like ...Hemagglutinin Ectodomain; Chain B - #10 / Hemagglutinin Ectodomain; Chain B / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / Immunoglobulins / Alpha-Beta Complex / Immunoglobulin-like / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Biological speciesInfluenza A virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHan, J. / Ward, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93019C00051 United States
CitationJournal: Sci Transl Med / Year: 2021
Title: First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes.
Authors: Jenna J Guthmiller / Julianna Han / Lei Li / Alec W Freyn / Sean T H Liu / Olivia Stovicek / Christopher T Stamper / Haley L Dugan / Micah E Tepora / Henry A Utset / Dalia J Bitar / Natalie ...Authors: Jenna J Guthmiller / Julianna Han / Lei Li / Alec W Freyn / Sean T H Liu / Olivia Stovicek / Christopher T Stamper / Haley L Dugan / Micah E Tepora / Henry A Utset / Dalia J Bitar / Natalie J Hamel / Siriruk Changrob / Nai-Ying Zheng / Min Huang / Florian Krammer / Raffael Nachbagauer / Peter Palese / Andrew B Ward / Patrick C Wilson /
Abstract: Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls ...Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls memory B cells that are specific to the conserved receptor-binding site (RBS) or lateral patch epitopes of the hemagglutinin (HA) head domain. Monoclonal antibodies (mAbs) generated against these epitopes are broadly neutralizing against H1N1 viruses spanning 40 years of viral evolution and provide potent protection in vivo. Lateral patch-targeting antibodies demonstrated near universal binding to H1 viruses, and RBS-binding antibodies commonly cross-reacted with H3N2 viruses and influenza B viruses. Lateral patch-targeting mAbs were restricted to expressing the variable heavy-chain gene VH3-23 with or without the variable kappa-chain gene VK1-33 and often had a Y-x-R motif within the heavy-chain complementarity determining region 3 to make key contacts with HA. Moreover, lateral patch antibodies that used both VH3-23 and VK1-33 maintained neutralizing capability with recent pH1N1 strains that acquired mutations near the lateral patch. RBS-binding mAbs used a diverse repertoire but targeted the RBS epitope similarly and made extensive contacts with the major antigenic site Sb. Together, our data indicate that RBS- and lateral patch-targeting clones are abundant within the human memory B cell pool, and universal vaccine strategies should aim to drive antibodies against both conserved head and stalk epitopes.
History
DepositionApr 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 28, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 20, 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 viewerMolecule:
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Assembly

Deposited unit
E: Hemagglutinin HA1 chain
L: Light chain of monoclonal antibody 045-09 2B05
H: Heavy chain of monoclonal antibody 045-09 2B05
D: Hemagglutinin HA2 chain
C: Hemagglutinin HA1 chain
J: Light chain of monoclonal antibody 045-09 2B05
G: Heavy chain of monoclonal antibody 045-09 2B05
A: Hemagglutinin HA2 chain
F: Hemagglutinin HA1 chain
K: Light chain of monoclonal antibody 045-09 2B05
I: Heavy chain of monoclonal antibody 045-09 2B05
B: Hemagglutinin HA2 chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)247,32924
Polymers243,62612
Non-polymers3,70212
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: ELISA and octet analyses confirmed that these components bind.
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Hemagglutinin ... , 2 types, 6 molecules ECFDAB

#1: Protein Hemagglutinin HA1 chain


Mass: 36729.402 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (strain swl A/California/04/2009 H1N1)
Strain: swl A/California/04/2009 H1N1 / Gene: HA / Cell line (production host): 293F / Production host: Homo sapiens (human) / References: UniProt: C3W5S1
#4: Protein Hemagglutinin HA2 chain


Mass: 19904.998 Da / Num. of mol.: 3 / Mutation: E47G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (strain swl A/California/04/2009 H1N1)
Strain: swl A/California/04/2009 H1N1 / Gene: HA / Cell line (production host): 293F / Production host: Homo sapiens (human) / References: UniProt: C3W5S1

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Antibody , 2 types, 6 molecules LJKHGI

#2: Antibody Light chain of monoclonal antibody 045-09 2B05


Mass: 11769.120 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: B cell / Cell line (production host): 293T / Production host: Homo sapiens (human)
#3: Antibody Heavy chain of monoclonal antibody 045-09 2B05


Mass: 12805.238 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: B cell / Cell line (production host): 293T / Production host: Homo sapiens (human)

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Sugars , 3 types, 12 molecules

#5: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#6: 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.: 3
Source method: isolated from a genetically manipulated source
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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: 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.: 6 / 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: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1CryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HACOMPLEX#1-#40MULTIPLE SOURCES
2monoclonal Fab 045-09 2B05COMPLEX#2-#31RECOMBINANT
3HemagglutininCOMPLEX#1, #41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Influenza A virus (strain swl A/California/04/2009 H1N1)641501
Source (recombinant)Organism: Homo sapiens (human) / Cell: 293F
Buffer solutionpH: 7.4 / Details: TBS + LMNG
SpecimenConc.: 0.75 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: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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 / Nominal magnification: 29000 X / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 49.27 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
2Leginonimage acquisition
13cryoSPARC23D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 27888 / Symmetry type: POINT

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