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- EMDB-40796: BG505 GT1.1 SOSIP in complex with NHP Fabs 12C11 and RM20A3 -

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Basic information

Entry
Database: EMDB / ID: EMD-40796
TitleBG505 GT1.1 SOSIP in complex with NHP Fabs 12C11 and RM20A3
Map dataSharpened map
Sample
  • Complex: BG505 GT1.1 SOSIP in complex with 12C11 Fab and RM20A3 Fab
    • Protein or peptide: BG505 GT1.1 SOSIP gp120
    • Protein or peptide: RM20A3 heavy chain variable region
    • Protein or peptide: RM20A3 light chain variable region
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: 12C11 heavy chain variable region
    • Protein or peptide: 12C11 light chain variable region
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsgermline targeting / HIV-1 Env / neutralizing antibody / non-human primate antibody / CD4 binding site / 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 / 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 speciesMacaca (macaques) / Human immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhang S / Torres JL / Ozorowski G / Ward AB
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01 AI110657 United States
CitationJournal: Sci Immunol / Year: 2024
Title: Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.
Authors: Tom G Caniels / Max Medina-Ramìrez / Shiyu Zhang / Sven Kratochvil / Yuejiao Xian / Ja-Hyun Koo / Ronald Derking / Jakob Samsel / Jelle van Schooten / Simone Pecetta / Edward Lamperti / ...Authors: Tom G Caniels / Max Medina-Ramìrez / Shiyu Zhang / Sven Kratochvil / Yuejiao Xian / Ja-Hyun Koo / Ronald Derking / Jakob Samsel / Jelle van Schooten / Simone Pecetta / Edward Lamperti / Meng Yuan / María Ríos Carrasco / Iván Del Moral Sánchez / Joel D Allen / Joey H Bouhuijs / Anila Yasmeen / Thomas J Ketas / Jonne L Snitselaar / Tom P L Bijl / Isabel Cuella Martin / Jonathan L Torres / Albert Cupo / Lisa Shirreff / Kenneth Rogers / Rosemarie D Mason / Mario Roederer / Kelli M Greene / Hongmei Gao / Catarina Mendes Silva / Isabel J L Baken / Ming Tian / Frederick W Alt / Bali Pulendran / Michael S Seaman / Max Crispin / Marit J van Gils / David C Montefiori / Adrian B McDermott / François J Villinger / Richard A Koup / John P Moore / Per Johan Klasse / Gabriel Ozorowski / Facundo D Batista / Ian A Wilson / Andrew B Ward / Rogier W Sanders /
Abstract: Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), ...Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.
History
DepositionMay 17, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40796.png

Downloads & links

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Map

FileDownload / File: emd_40796.map.gz / Format: CCP4 / Size: 222.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 388 pix.
= 391.492 Å		1.01 Å/pix.
x 388 pix.
= 391.492 Å		1.01 Å/pix.
x 388 pix.
= 391.492 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.009 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.63977 - 2.6837301
Average (Standard dev.)-0.00029284353 (±0.041955277)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions388388388
Spacing388388388
CellA=B=C: 391.49197 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_40796_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_40796_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_40796_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : BG505 GT1.1 SOSIP in complex with 12C11 Fab and RM20A3 Fab

EntireName: BG505 GT1.1 SOSIP in complex with 12C11 Fab and RM20A3 Fab
Components
  • Complex: BG505 GT1.1 SOSIP in complex with 12C11 Fab and RM20A3 Fab
    • Protein or peptide: BG505 GT1.1 SOSIP gp120
    • Protein or peptide: RM20A3 heavy chain variable region
    • Protein or peptide: RM20A3 light chain variable region
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: 12C11 heavy chain variable region
    • Protein or peptide: 12C11 light chain variable region
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: BG505 GT1.1 SOSIP in complex with 12C11 Fab and RM20A3 Fab

SupramoleculeName: BG505 GT1.1 SOSIP in complex with 12C11 Fab and RM20A3 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 720 KDa

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Macromolecule #1: BG505 GT1.1 SOSIP gp120

MacromoleculeName: BG505 GT1.1 SOSIP gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 57.27548 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARAENLW VTVYYGVPVW KDAETTLFCA SDAKAYETKK HNVWATHACV PTDPNPQEI HLENVTEEFN MWKNNMVEQM HTDIISLWDQ SLKPCVKLTP LCVTLQCTNV TNNITDDMRG ELKNCSFNMT T ELRDKRQK ...String:
MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARAENLW VTVYYGVPVW KDAETTLFCA SDAKAYETKK HNVWATHACV PTDPNPQEI HLENVTEEFN MWKNNMVEQM HTDIISLWDQ SLKPCVKLTP LCVTLQCTNV TNNITDDMRG ELKNCSFNMT T ELRDKRQK VHALFYKLDI VPINENQNTS YRLINCNTAA ITQACPKVSF EPIPIHYCAP AGFAILKCKD KKFNGTGPCP SV STVQCTH GIKPVVSTQL LLNGSLAEEE VMIRSKDIRN NAKNILVQFN TPVQINCTRP NNNTRKSIRI GPGQWFYATG DII GDIRQA HCNVSKATWN ETLGKVVKQL RKHFGNNTII RFANSSGGDL EVTTHSFNCG GEFFYCDTSG LFNSTWISNT SVQG SNSTG SNDSITLPCR IKQIINMWQR IGQAMYAPPI QGVIRCVSNI TGLILTRDGG STDSTTETFR PSGGDMRDNW RSELY KYKV VKIEPLGVAP TRCKRRVVGR RRRRR

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Macromolecule #2: RM20A3 heavy chain variable region

MacromoleculeName: RM20A3 heavy chain variable region / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 13.511111 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLVETGGG LVQPGGSLKL SCRASGYTFS SFAMSWVRQA PGKGLEWVSL INDRGGLTFY VDSVKGRFTI SRDNSKNTLS LQMHSLRDG DTAVYYCATG GMSSALQSSK YYFDFWGQGA LVTVSS

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Macromolecule #3: RM20A3 light chain variable region

MacromoleculeName: RM20A3 light chain variable region / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 11.755821 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSALTQPPSV SGSPGQSVTI SCTGTSSDIG SYNYVSWYQQ HPGKAPKLMI YDVTQRPSGV SDRFSGSKSG NTASLTISGL QADDEADYY CSAYAGRQTF YIFGGGTRLT VL

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Macromolecule #4: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 4 / 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 #5: 12C11 heavy chain variable region

MacromoleculeName: 12C11 heavy chain variable region / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 14.244822 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLQESGPG LVKPSETLSL TCAVSGNPVT AGFDWTWIRQ SPGKGLEWIG HIYGASGSTN YNPSLESRVT ISRDASRNQF SLKLTTVTA ADTAVYYCAR RGGDHRYSRM LTFTFTNFDF WGQGVLVTVS S

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Macromolecule #6: 12C11 light chain variable region

MacromoleculeName: 12C11 light chain variable region / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 11.475475 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSVLTQPPSV SEAARKSVSI SCSGSDSNIG SNSVSWFQQF PGTAPKLLIH FNNQRASGVS DRFSGSKSGT SASLAISGLQ TDDEADYYC AAWDDSLTAA VFGTGTRLTV L

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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: 42 / 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

Concentration8 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
50.0 mMTris
150.0 mMSodium chlorideNaCl
0.06 mMn-Dodecyl-B-D-Maltopyranoside

Details: Detergent added shortly before freezing
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 5627 / Average electron dose: 50.3 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 190000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Startup modelType of model: OTHER / Details: cryoSPARC ab initio
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Software - details: Non-uniform refinement / Number images used: 456166
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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