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- EMDB-27139: Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited,... -

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Basic information

Entry
Database: EMDB / ID: EMD-27139
TitleCryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer
Map datasharpened map
Sample
  • Complex: Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer
    • Complex: 1B06 Fab with NC99 HA trimer
      • Protein or peptide: Hemagglutinin HA2 chain
      • Protein or peptide: Hemagglutinin HA1 chain
      • Protein or peptide: 1B06 Heavy Chain
      • Protein or peptide: 1B06 Light Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / 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 / 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
Hemagglutinin / Hemagglutinin
Similarity search - Component
Biological speciesInfluenza A virus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.96 Å
AuthorsGorman J / Kwong PD
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
Other privateSimons Foundation (SF349247) United States
CitationJournal: Sci Transl Med / Year: 2023
Title: An influenza H1 hemagglutinin stem-only immunogen elicits a broadly cross-reactive B cell response in humans.
Authors: Sarah F Andrews / Lauren Y Cominsky / Geoffrey D Shimberg / Rebecca A Gillespie / Jason Gorman / Julie E Raab / Joshua Brand / Adrian Creanga / Suprabhath R Gajjala / Sandeep Narpala / ...Authors: Sarah F Andrews / Lauren Y Cominsky / Geoffrey D Shimberg / Rebecca A Gillespie / Jason Gorman / Julie E Raab / Joshua Brand / Adrian Creanga / Suprabhath R Gajjala / Sandeep Narpala / Crystal S F Cheung / Darcy R Harris / Tongqing Zhou / Ingelise Gordon / LaSonji Holman / Floreliz Mendoza / Katherine V Houser / Grace L Chen / John R Mascola / Barney S Graham / Peter D Kwong / Alicia Widge / Lesia K Dropulic / Julie E Ledgerwood / Masaru Kanekiyo / Adrian B McDermott /
Abstract: Current yearly seasonal influenza vaccines primarily induce an antibody response directed against the immunodominant but continually diversifying hemagglutinin (HA) head region. These antibody ...Current yearly seasonal influenza vaccines primarily induce an antibody response directed against the immunodominant but continually diversifying hemagglutinin (HA) head region. These antibody responses provide protection against the vaccinating strain but little cross-protection against other influenza strains or subtypes. To focus the immune response on subdominant but more conserved epitopes on the HA stem that might protect against a broad range of influenza strains, we developed a stabilized H1 stem immunogen lacking the immunodominant head displayed on a ferritin nanoparticle (H1ssF). Here, we evaluated the B cell response to H1ssF in healthy adults ages 18 to 70 in a phase 1 clinical trial (NCT03814720). We observed both a strong plasmablast response and sustained elicitation of cross-reactive HA stem-specific memory B cells after vaccination with H1ssF in individuals of all ages. The B cell response was focused on two conserved epitopes on the H1 stem, with a highly restricted immunoglobulin repertoire unique to each epitope. On average, two-thirds of the B cell and serological antibody response recognized a central epitope on the H1 stem and exhibited broad neutralization across group 1 influenza virus subtypes. The remaining third recognized an epitope near the viral membrane anchor and was largely limited to H1 strains. Together, we demonstrate that an H1 HA immunogen lacking the immunodominant HA head produces a robust and broadly neutralizing HA stem-directed B cell response.
History
DepositionMay 27, 2022-
Header (metadata) releaseApr 12, 2023-
Map releaseApr 12, 2023-
UpdateMay 3, 2023-
Current statusMay 3, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27139.png

Downloads & links

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Map

FileDownload / File: emd_27139.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.0825 Å
Density
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-0.9085625 - 2.2275305
Average (Standard dev.)0.013696766 (±0.08581096)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 324.75 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27139_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: unsharpened map

Fileemd_27139_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: density modified with resolve

Fileemd_27139_additional_2.map
Annotationdensity modified with resolve
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_27139_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_27139_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited,...

EntireName: Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer
Components
  • Complex: Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer
    • Complex: 1B06 Fab with NC99 HA trimer
      • Protein or peptide: Hemagglutinin HA2 chain
      • Protein or peptide: Hemagglutinin HA1 chain
      • Protein or peptide: 1B06 Heavy Chain
      • Protein or peptide: 1B06 Light Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited,...

SupramoleculeName: Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: 1B06 Fab with NC99 HA trimer

SupramoleculeName: 1B06 Fab with NC99 HA trimer / type: complex / ID: 2 / Chimera: Yes / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Influenza A virus

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Macromolecule #1: Hemagglutinin HA2 chain

MacromoleculeName: Hemagglutinin HA2 chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus
Molecular weightTheoretical: 25.263104 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GLFGAIAGFI EGGWTGMVDG WYGYHHQNEQ GSGYAADQKS TQNAINCITN KVNSVIEKMN TQFTAVGKEF NKLERRMENL NKKVDDGFL DIWTYNAELL VLLENERTLD FHDSNVKNLY EKVKSQLKNN AKEIGNGCFE FYHKCNNECM ESVKNGTYDY P KYSEESKL ...String:
GLFGAIAGFI EGGWTGMVDG WYGYHHQNEQ GSGYAADQKS TQNAINCITN KVNSVIEKMN TQFTAVGKEF NKLERRMENL NKKVDDGFL DIWTYNAELL VLLENERTLD FHDSNVKNLY EKVKSQLKNN AKEIGNGCFE FYHKCNNECM ESVKNGTYDY P KYSEESKL NREKIDGVSG RLVPRGSPGS GYIPEAPRDG QAYVRKDGEW VLLSTFLGHH HHHH

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Macromolecule #2: Hemagglutinin HA1 chain

MacromoleculeName: Hemagglutinin HA1 chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus
Molecular weightTheoretical: 36.407852 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DTICIGYHAN NSTDTVDTVC EKNVTVTHSV NLLEDSHNGK LCLLKGIAPL QLGNCSVAGW ILGNPECELL ISKESWSYIV ETPNPENGT CYPGYFADYE ELREQLSSVS SFERFEIFPK ESSWPNHTVT GVSASCSHNG KSSFYRNLLW LTGKNGLYPN L SKSYVNNK ...String:
DTICIGYHAN NSTDTVDTVC EKNVTVTHSV NLLEDSHNGK LCLLKGIAPL QLGNCSVAGW ILGNPECELL ISKESWSYIV ETPNPENGT CYPGYFADYE ELREQLSSVS SFERFEIFPK ESSWPNHTVT GVSASCSHNG KSSFYRNLLW LTGKNGLYPN L SKSYVNNK EKEVLVLWGV HHPPNIGNQR ALYHTENAYV SVVSSHYSRR FTPEIAKRPK VRDQEGRINY YWTLLEPGDT II FEANGNL IAPWYAFALS RGFGSGIITS NAPMDECDAK CQTPQGAINS SLPFQNVHPV TIGECPKYVR SAKLRMVTGL RNI PSIQSR

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Macromolecule #3: 1B06 Heavy Chain

MacromoleculeName: 1B06 Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.499133 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLLESGGG LVRPGGSLRL SCKASGFSFS RHGLSWVRQA PGKGLEWVSS ISGSSLSRYY ADSVKGRFTI SRDNSQNTLY LQMNSLRVE DTAVFYCVKD RLDTAVPRGW FDSWGQGILV TVSS

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Macromolecule #4: 1B06 Light Chain

MacromoleculeName: 1B06 Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.77808 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EIVMTQSPAT LSVSPGDRAT LSCRASQSVS TELAWYQQKP GQAPRLLIYG ASTRATDIPA RFSGSGSGTE FTLTISSLQS EDFAVYFCQ QYNNWPPITF GQGTRLEIK

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 21 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: C-flat-1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV
Details1B06 in complex with a stabilized NC99 HA trimer

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average exposure time: 2.0 sec. / Average electron dose: 70.72 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 2.15)
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.96 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.15) / Number images used: 73396

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Atomic model buiding 1

Initial modelPDB ID:

7mfg

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8d21:
Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer

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