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- EMDB-29880: Cryo-EM structure of vFP49.02 Fab in complex with HIV-1 Env BG505... -

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Basic information

Entry
Database: EMDB / ID: EMD-29880
TitleCryo-EM structure of vFP49.02 Fab in complex with HIV-1 Env BG505 DS-SOSIP.664 (conformation 1)
Map dataSharpened
Sample
  • Complex: vFP49.02 Fab in complex with BG505 DS-SOSIP.664
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: vFP49.02 heavy chain
    • Protein or peptide: vFP49.02 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHIV-1 / fusion peptide / antibody / SOSIP / IMMUNE SYSTEM
Function / homology
Function and homology information


positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope ...positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / 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 / structural molecule activity / identical protein binding / plasma membrane
Similarity search - Function
Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120
Similarity search - Domain/homology
Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1 / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.66 Å
AuthorsChangela A / Gorman J / Kwong PD
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
Simons FoundationSF349247 United States
CitationJournal: J Virol / Year: 2023
Title: Diverse Murine Vaccinations Reveal Distinct Antibody Classes to Target Fusion Peptide and Variation in Peptide Length to Improve HIV Neutralization.
Authors: Mallika Sastry / Anita Changela / Jason Gorman / Kai Xu / Gwo-Yu Chuang / Chen-Hsiang Shen / Cheng Cheng / Hui Geng / Sijy O'Dell / Li Ou / Reda Rawi / Mateo Reveiz / Guillaume B E Stewart- ...Authors: Mallika Sastry / Anita Changela / Jason Gorman / Kai Xu / Gwo-Yu Chuang / Chen-Hsiang Shen / Cheng Cheng / Hui Geng / Sijy O'Dell / Li Ou / Reda Rawi / Mateo Reveiz / Guillaume B E Stewart-Jones / Shuishu Wang / Baoshan Zhang / Tongqing Zhou / Andrea Biju / Michael Chambers / Xuejun Chen / Angela R Corrigan / Bob C Lin / Mark K Louder / Krisha McKee / Alexandra F Nazzari / Adam S Olia / Danealle K Parchment / Edward K Sarfo / Tyler Stephens / Jonathan Stuckey / Yaroslav Tsybovsky / Raffaello Verardi / Yiran Wang / Cheng-Yan Zheng / Yuling Chen / Nicole A Doria-Rose / Adrian B McDermott / John R Mascola / Peter D Kwong /
Abstract: While neutralizing antibodies that target the HIV-1 fusion peptide have been elicited in mice by vaccination, antibodies reported thus far have been from only a single antibody class that could ...While neutralizing antibodies that target the HIV-1 fusion peptide have been elicited in mice by vaccination, antibodies reported thus far have been from only a single antibody class that could neutralize ~30% of HIV-1 strains. To explore the ability of the murine immune system to generate cross-clade neutralizing antibodies and to investigate how higher breadth and potency might be achieved, we tested 17 prime-boost regimens that utilized diverse fusion peptide-carrier conjugates and HIV-1 envelope trimers with different fusion peptides. We observed priming in mice with fusion peptide-carrier conjugates of variable peptide length to elicit higher neutralizing responses, a result we confirmed in guinea pigs. From vaccinated mice, we isolated 21 antibodies, belonging to 4 distinct classes of fusion peptide-directed antibodies capable of cross-clade neutralization. Top antibodies from each class collectively neutralized over 50% of a 208-strain panel. Structural analyses - both X-ray and cryo-EM - revealed each antibody class to recognize a distinct conformation of fusion peptide and to have a binding pocket capable of accommodating diverse fusion peptides. Murine vaccinations can thus elicit diverse neutralizing antibodies, and altering peptide length during prime can improve the elicitation of cross-clade responses targeting the fusion peptide site of HIV-1 vulnerability. The HIV-1 fusion peptide has been identified as a site for elicitation of broadly neutralizing antibodies, with prior studies demonstrating that priming with fusion peptide-based immunogens and boosting with soluble envelope (Env) trimers can elicit cross-clade HIV-1-neutralizing responses. To improve the neutralizing breadth and potency of fusion peptide-directed responses, we evaluated vaccine regimens that incorporated diverse fusion peptide-conjugates and Env trimers with variation in fusion peptide length and sequence. We found that variation in peptide length during prime elicits enhanced neutralizing responses in mice and guinea pigs. We identified vaccine-elicited murine monoclonal antibodies from distinct classes capable of cross-clade neutralization and of diverse fusion peptide recognition. Our findings lend insight into improved immunogens and regimens for HIV-1 vaccine development.
History
DepositionFeb 22, 2023-
Header (metadata) releaseApr 19, 2023-
Map releaseApr 19, 2023-
UpdateJun 14, 2023-
Current statusJun 14, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29880.png

Downloads & links

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Map

FileDownload / File: emd_29880.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened
Voxel sizeX=Y=Z: 1.07325 Å
Density
Contour LevelBy AUTHOR: 0.27
Minimum - Maximum-0.12830254 - 1.1657244
Average (Standard dev.)0.009637866 (±0.05278509)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 343.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened

Fileemd_29880_additional_1.map
AnnotationUnsharpened
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_29880_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29880_half_map_2.map
Projections & Slices
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Sample components

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Entire : vFP49.02 Fab in complex with BG505 DS-SOSIP.664

EntireName: vFP49.02 Fab in complex with BG505 DS-SOSIP.664
Components
  • Complex: vFP49.02 Fab in complex with BG505 DS-SOSIP.664
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: vFP49.02 heavy chain
    • Protein or peptide: vFP49.02 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: vFP49.02 Fab in complex with BG505 DS-SOSIP.664

SupramoleculeName: vFP49.02 Fab in complex with BG505 DS-SOSIP.664 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17.146482 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVGIGAVFLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEA QQHLLKLTVW GIKQLQARVL AVERYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALD

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Macromolecule #2: Envelope glycoprotein gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 54.086324 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT ...String:
AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT SACTQACPKV SFEPIPIHYC APAGFAILKC KDKKFNGTGP CPSVSTVQCT HGIKPVVSTQ LLLNGSLAEE EV MIRSENI TNNAKNILVQ FNTPVQINCT RPNNNTRKSI RIGPGQAFYA TGDIIGDIRQ AHCNVSKATW NETLGKVVKQ LRK HFGNNT IIRFANSSGG DLEVTTHSFN CGGEFFYCNT SGLFNSTWIS NTSVQGSNST GSNDSITLPC RIKQIINMWQ RIGQ CMYAP PIQGVIRCVS NITGLILTRD GGSTNSTTET FRPGGGDMRD NWRSELYKYK VVKIEPLGVA PTRCKRRVVG RRRRR R

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Macromolecule #3: vFP49.02 heavy chain

MacromoleculeName: vFP49.02 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.020025 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVMLVESGGG LVKPGGSLKL SCEASGFSFG FYSLSWVRQT PEKRLEWVAT IAGSGVGGQT YYPDSVKGRF TISRDNAKNT LYLQMSSLR SEDTAVFYCA RHGEGKYGSN FAYWGQGTTL TVSSASTTPP SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP V TVTWNSGS ...String:
EVMLVESGGG LVKPGGSLKL SCEASGFSFG FYSLSWVRQT PEKRLEWVAT IAGSGVGGQT YYPDSVKGRF TISRDNAKNT LYLQMSSLR SEDTAVFYCA RHGEGKYGSN FAYWGQGTTL TVSSASTTPP SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP V TVTWNSGS LSSGVHTFPA VLQSDLYTLS SSVTVPSSTW PSETVTCNVA HPASSTKVDK KIVPRDCDKG LEVLFQG

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Macromolecule #4: vFP49.02 light chain

MacromoleculeName: vFP49.02 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.620969 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVVLTQSPAT LSVTPGDSVS LSCRASQTIS DNLHWYLQKS HESPRLLIKY SSQSISGIPS RFSGSGSGTD FTLNINSVET EDFGMYFCQ QTNSWPLTFG AGTKLELKRT DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
DVVLTQSPAT LSVTPGDSVS LSCRASQTIS DNLHWYLQKS HESPRLLIKY SSQSISGIPS RFSGSGSGTD FTLNINSVET EDFGMYFCQ QTNSWPLTFG AGTKLELKRT DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 15 / 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

BufferpH: 7.4
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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 69.99 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.66 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 17037

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Atomic model buiding 1

Initial model(Chain: PDB, experimental model, PDB, experimental model)
Output model

PDB-8g9w:
Cryo-EM structure of vFP49.02 Fab in complex with HIV-1 Env BG505 DS-SOSIP.664 (conformation 1)

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