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- EMDB-29836: vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer -

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Basic information

Entry
Database: EMDB / ID: EMD-29836
TitlevFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer
Map datasharpened
Sample
  • Complex: vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: vFP52.02 Heavy
    • Protein or peptide: vFP52.02 Light
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHIV-1 / SOSIP / Vaccine / IMMUNE SYSTEM / fusion peptide / FP / VIRAL PROTEIN
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 / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / 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 / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / 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: 3.99 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)
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 17, 2023-
Header (metadata) releaseApr 19, 2023-
Map releaseApr 19, 2023-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29836.png

Downloads & links

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Map

FileDownload / File: emd_29836.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 320 pix.
= 343.456 Å		1.07 Å/pix.
x 320 pix.
= 343.456 Å		1.07 Å/pix.
x 320 pix.
= 343.456 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0733 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-0.35210645 - 1.5599049
Average (Standard dev.)0.0104247695 (±0.06078071)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 343.456 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29836_msk_1.map
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Additional map: unsharpened

Fileemd_29836_additional_1.map
Annotationunsharpened
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Half map: half map a

Fileemd_29836_half_map_1.map
Annotationhalf map a
Projections & Slices
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Half map: half map b

Fileemd_29836_half_map_2.map
Annotationhalf map b
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Sample components

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Entire : vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer

EntireName: vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer
Components
  • Complex: vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: vFP52.02 Heavy
    • Protein or peptide: vFP52.02 Light
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer

SupramoleculeName: vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer
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 gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 1 / 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

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #2: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 2 / 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

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #3: vFP52.02 Heavy

MacromoleculeName: vFP52.02 Heavy / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.125581 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DVQLQESGPG LVKPSQSLSL TCSVTGYSIT SAYYWNWIRQ FPGKKLEWMG YLLYDGSTGY NPSLKNRISI TRDTSKNQFF LKLNSVTPE DTATYYCSRE GNNRSYWGQG TTLIVSS

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Macromolecule #4: vFP52.02 Light

MacromoleculeName: vFP52.02 Light / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.951338 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIVMTQSHRF MSTSVGDRVS ITCKASQSVD TAVAWYQQKP GQSPKLLIYW ASTRHPGVPD RFTGSGSGTD FILTISNVQS EDLADYFCH QFDRYPLTFG DGTKLELK

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Macromolecule #11: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 11 / Number of copies: 35 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average exposure time: 10.0 sec. / Average electron dose: 69.87 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.99 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 49028
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3)

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Atomic model buiding 1

Initial modelPDB ID:

7lpn


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8g85:
vFP52.02 Fab in complex with BG505 DS-SOSIP Env trimer

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