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- EMDB-40825: 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fa... -

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Entry
Database: EMDB / ID: EMD-40825
Title10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fab W6-10
Map data
Sample
  • Complex: 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fab W6-10
    • Complex: W6-10 mouse Fab heavy chain, W6-10 mouse light chain
      • Protein or peptide: W6-10 mouse Fab heavy chain
      • Protein or peptide: W6-10 mouse light chain
    • Complex: 10E8-GT10.2 immunogen
      • Protein or peptide: 10E8-GT10.2 immunogen
    • Complex: 10E8 Fab heavy chain, 10E8 light chain
      • Protein or peptide: 10E8 Fab heavy chain
      • Protein or peptide: 10E8 light chain
KeywordsHIV / Germline targeting / MPER / broadly neutralizing antibody / vaccine design / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Biological speciesMus musculus (house mouse) / synthetic construct (others) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsHuang J / Ozorowski G / Ward AB
Funding support United States, 2 items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationINV-002916 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UM1 AI144462 United States
CitationJournal: Nat Immunol / Year: 2024
Title: Vaccination induces broadly neutralizing antibody precursors to HIV gp41.
Authors: Torben Schiffner / Ivy Phung / Rashmi Ray / Adriana Irimia / Ming Tian / Olivia Swanson / Jeong Hyun Lee / Chang-Chun D Lee / Ester Marina-Zárate / So Yeon Cho / Jiachen Huang / Gabriel ...Authors: Torben Schiffner / Ivy Phung / Rashmi Ray / Adriana Irimia / Ming Tian / Olivia Swanson / Jeong Hyun Lee / Chang-Chun D Lee / Ester Marina-Zárate / So Yeon Cho / Jiachen Huang / Gabriel Ozorowski / Patrick D Skog / Andreia M Serra / Kimmo Rantalainen / Joel D Allen / Sabyasachi Baboo / Oscar L Rodriguez / Sunny Himansu / Jianfu Zhou / Jonathan Hurtado / Claudia T Flynn / Katherine McKenney / Colin Havenar-Daughton / Swati Saha / Kaitlyn Shields / Steven Schulze / Melissa L Smith / Chi-Hui Liang / Laura Toy / Simone Pecetta / Ying-Cing Lin / Jordan R Willis / Fabian Sesterhenn / Daniel W Kulp / Xiaozhen Hu / Christopher A Cottrell / Xiaoya Zhou / Jennifer Ruiz / Xuesong Wang / Usha Nair / Kathrin H Kirsch / Hwei-Ling Cheng / Jillian Davis / Oleksandr Kalyuzhniy / Alessia Liguori / Jolene K Diedrich / Julia T Ngo / Vanessa Lewis / Nicole Phelps / Ryan D Tingle / Skye Spencer / Erik Georgeson / Yumiko Adachi / Michael Kubitz / Saman Eskandarzadeh / Marc A Elsliger / Rama R Amara / Elise Landais / Bryan Briney / Dennis R Burton / Diane G Carnathan / Guido Silvestri / Corey T Watson / John R Yates / James C Paulson / Max Crispin / Gevorg Grigoryan / Andrew B Ward / Devin Sok / Frederick W Alt / Ian A Wilson / Facundo D Batista / Shane Crotty / William R Schief /
Abstract: A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design ...A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
History
DepositionMay 19, 2023-
Header (metadata) releaseMay 22, 2024-
Map releaseMay 22, 2024-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40825.png

Downloads & links

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Map

FileDownload / File: emd_40825.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.725 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.27390212 - 0.40287742
Average (Standard dev.)0.000028755474 (±0.0076589696)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 301.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_40825_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40825_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_40825_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fa...

EntireName: 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fab W6-10
Components
  • Complex: 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fab W6-10
    • Complex: W6-10 mouse Fab heavy chain, W6-10 mouse light chain
      • Protein or peptide: W6-10 mouse Fab heavy chain
      • Protein or peptide: W6-10 mouse light chain
    • Complex: 10E8-GT10.2 immunogen
      • Protein or peptide: 10E8-GT10.2 immunogen
    • Complex: 10E8 Fab heavy chain, 10E8 light chain
      • Protein or peptide: 10E8 Fab heavy chain
      • Protein or peptide: 10E8 light chain

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Supramolecule #1: 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fa...

SupramoleculeName: 10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fab W6-10
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: W6-10 mouse Fab heavy chain, W6-10 mouse light chain

SupramoleculeName: W6-10 mouse Fab heavy chain, W6-10 mouse light chain / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #3: 10E8-GT10.2 immunogen

SupramoleculeName: 10E8-GT10.2 immunogen / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: synthetic construct (others)

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Supramolecule #4: 10E8 Fab heavy chain, 10E8 light chain

SupramoleculeName: 10E8 Fab heavy chain, 10E8 light chain / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: W6-10 mouse Fab heavy chain

MacromoleculeName: W6-10 mouse Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.97401 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVTLKESGPG ILQPSQTLSL TCSFSGFSLS TFGMGVGWIR QPSGKGLEWL AHIWWDDDKF YNPALKSRLT ISKDTSKNQV FLKIANVDT ADTATYYCAR IGEDYFLDVW GKGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG ...String:
QVTLKESGPG ILQPSQTLSL TCSFSGFSLS TFGMGVGWIR QPSGKGLEWL AHIWWDDDKF YNPALKSRLT ISKDTSKNQV FLKIANVDT ADTATYYCAR IGEDYFLDVW GKGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSCDK

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Macromolecule #2: W6-10 mouse light chain

MacromoleculeName: W6-10 mouse light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.417891 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPAS LSASVGETVT ITCRASGNIH NYLAWYQQKQ GKSPQLLVYN AKTLADGVPS RFSGSGSGTQ YSLKINSLQP EDFGSYYCQ HFWSAPYTFG GGTNLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPAS LSASVGETVT ITCRASGNIH NYLAWYQQKQ GKSPQLLVYN AKTLADGVPS RFSGSGSGTQ YSLKINSLQP EDFGSYYCQ HFWSAPYTFG GGTNLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: 10E8-GT10.2 immunogen

MacromoleculeName: 10E8-GT10.2 immunogen / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 21.07375 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
TGNVTQEDII RALASPLIKD GMVDEDFAEY VIARENRSPT GLQAKGVGVA IPHTLGDYVR DNAISVGILD KPVNFSGWYQ SPDPVPVRV VFMLAGRTWD DIVIVLKWIK DVILDEEFMK RLLNMSDEEI YRQIYTRISK APNLSGINFS REYVRHLNGS G GSGLNDIF EAQKIEWHEG SGGHHHHHH

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Macromolecule #4: 10E8 Fab heavy chain

MacromoleculeName: 10E8 Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.175193 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVKPGGSLRL SCSASGFDFD NAWMTWVRQP PGKGLEWVGR ITGPGEGWSV DYAAPVEGRF TISRLNSINF LYLEMNNLR MEDSGLYFCA RTGKYYDFWS GYPPGEEYFQ DWGRGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV ...String:
EVQLVESGGG LVKPGGSLRL SCSASGFDFD NAWMTWVRQP PGKGLEWVGR ITGPGEGWSV DYAAPVEGRF TISRLNSINF LYLEMNNLR MEDSGLYFCA RTGKYYDFWS GYPPGEEYFQ DWGRGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSC

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Macromolecule #5: 10E8 light chain

MacromoleculeName: 10E8 light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.959434 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SYELTQETGV SVALGRTVTI TCRGDSLRSH YASWYQKKPG QAPILLFYGK NNRPSGVPDR FSGSASGNRA SLTISGAQAE DDAEYYCSS RDKSGSRLSV FGGGTKLTVL GQPKAAPSVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK A GVETTTPS ...String:
SYELTQETGV SVALGRTVTI TCRGDSLRSH YASWYQKKPG QAPILLFYGK NNRPSGVPDR FSGSASGNRA SLTISGAQAE DDAEYYCSS RDKSGSRLSV FGGGTKLTVL GQPKAAPSVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK A GVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS

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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

Concentration2.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
50.0 mMTris
150.0 mMsodium chloride
0.005 mMLauryl Maltose Neopentyl Glycol
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.7000000000000001 µm
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 53.0 e/Å2

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Image processing

Startup modelType of model: INSILICO MODEL / Details: Cryosparc Ab-initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 56628
FSC plot (resolution estimation)

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