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- EMDB-24072: Ab1245 Fab in complex with BG505 SOSIP.664 and 8ANC195 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-24072
TitleAb1245 Fab in complex with BG505 SOSIP.664 and 8ANC195 Fab
Map data
Sample
  • Complex: Complex of NHP-isolated Ab1245 Fab and bNAb 8ANC195 G52K5 Fab bound to BG505 SOSIP.664 trimer
    • Complex: 8ANC195 G52K5 Fab
      • Protein or peptide: 8ANC195 G52K5 Fab heavy chain
      • Protein or peptide: 8ANC195 G52K5 Fab light chain
    • Complex: Ab1245 Fab
      • Protein or peptide: Ab1245 Fab heavy chain
      • Protein or peptide: Ab1245 Fab light chain
    • Complex: BG505 SOSIP.664 trimer
      • Protein or peptide: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
      • Protein or peptide: Envelope glycoprotein BG505 SOSIP.664 gp120
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
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 / structural molecule activity / virion attachment to host cell / host cell plasma membrane / 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 speciesHomo sapiens (human) / Macaca mulatta (Rhesus monkey) / Human immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsAbernathy ME / Bjorkman PJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HIVRAD P01 AI100148 United States
Bill & Melinda Gates FoundationCAVD INV-002143 United States
CitationJournal: NPJ Vaccines / Year: 2021
Title: Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope.
Authors: Morgan E Abernathy / Harry B Gristick / Jost Vielmetter / Jennifer R Keeffe / Priyanthi N P Gnanapragasam / Yu E Lee / Amelia Escolano / Rajeev Gautam / Michael S Seaman / Malcolm A Martin / ...Authors: Morgan E Abernathy / Harry B Gristick / Jost Vielmetter / Jennifer R Keeffe / Priyanthi N P Gnanapragasam / Yu E Lee / Amelia Escolano / Rajeev Gautam / Michael S Seaman / Malcolm A Martin / Michel C Nussenzweig / Pamela J Bjorkman /
Abstract: HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report ...HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7 Å cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, raising the possibility that only two fusion peptides per trimer are required for viral-host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide.
History
DepositionMay 19, 2021-
Header (metadata) releaseOct 27, 2021-
Map releaseOct 27, 2021-
UpdateNov 3, 2021-
Current statusNov 3, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0154
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0154
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mxe
  • Surface level: 0.0154
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7mxe
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24072.png

Downloads & links

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Map

FileDownload / File: emd_24072.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.8654 Å
Density
Contour LevelBy AUTHOR: 0.0154 / Movie #1: 0.0154
Minimum - Maximum-0.06302578 - 0.107740745
Average (Standard dev.)0.00025866996 (±0.0043946602)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 290.7744 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.865398809523810.865398809523810.86539880952381
M x/y/z336336336
origin x/y/z0.0000.0000.000
length x/y/z290.774290.774290.774
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS336336336
D min/max/mean-0.0630.1080.000

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Supplemental data

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Mask #1

Fileemd_24072_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: blurred map

Fileemd_24072_additional_1.map
Annotationblurred map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_24072_half_map_1.map
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_24072_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Complex of NHP-isolated Ab1245 Fab and bNAb 8ANC195 G52K5 Fab bou...

EntireName: Complex of NHP-isolated Ab1245 Fab and bNAb 8ANC195 G52K5 Fab bound to BG505 SOSIP.664 trimer
Components
  • Complex: Complex of NHP-isolated Ab1245 Fab and bNAb 8ANC195 G52K5 Fab bound to BG505 SOSIP.664 trimer
    • Complex: 8ANC195 G52K5 Fab
      • Protein or peptide: 8ANC195 G52K5 Fab heavy chain
      • Protein or peptide: 8ANC195 G52K5 Fab light chain
    • Complex: Ab1245 Fab
      • Protein or peptide: Ab1245 Fab heavy chain
      • Protein or peptide: Ab1245 Fab light chain
    • Complex: BG505 SOSIP.664 trimer
      • Protein or peptide: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
      • Protein or peptide: Envelope glycoprotein BG505 SOSIP.664 gp120
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of NHP-isolated Ab1245 Fab and bNAb 8ANC195 G52K5 Fab bou...

SupramoleculeName: Complex of NHP-isolated Ab1245 Fab and bNAb 8ANC195 G52K5 Fab bound to BG505 SOSIP.664 trimer
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Molecular weightTheoretical: 500 KDa

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Supramolecule #2: 8ANC195 G52K5 Fab

SupramoleculeName: 8ANC195 G52K5 Fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: Ab1245 Fab

SupramoleculeName: Ab1245 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #5-#6
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #4: BG505 SOSIP.664 trimer

SupramoleculeName: BG505 SOSIP.664 trimer / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Human immunodeficiency virus 1
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Macromolecule #1: 8ANC195 G52K5 Fab heavy chain

MacromoleculeName: 8ANC195 G52K5 Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.153283 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QIHLVQSGTE VKKPGSSVTV SCKAYGVNTF GLYAVNWVRQ APGQSLEYIG QIWRWKSSAS HHFRGRVLIS AVDLTGSSPP ISSLEIKNL TSDDTAVYFC TTTSTYDRWS GLHHDGVMAF SSWGQGTLIS VSAASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP ...String:
QIHLVQSGTE VKKPGSSVTV SCKAYGVNTF GLYAVNWVRQ APGQSLEYIG QIWRWKSSAS HHFRGRVLIS AVDLTGSSPP ISSLEIKNL TSDDTAVYFC TTTSTYDRWS GLHHDGVMAF SSWGQGTLIS VSAASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HH HHHH

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Macromolecule #2: 8ANC195 G52K5 Fab light chain

MacromoleculeName: 8ANC195 G52K5 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.460047 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPST LSASTGDTVR ISCRASQSIT GNWVAWYQQR PGKAPRLLIY RGAALLGGVP SRFRGSAAGT DFTLTIGNLQ AEDFGTFYC QQYDTYPGTF GQGTKVEVKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPST LSASTGDTVR ISCRASQSIT GNWVAWYQQR PGKAPRLLIY RGAALLGGVP SRFRGSAAGT DFTLTIGNLQ AEDFGTFYC QQYDTYPGTF GQGTKVEVKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #3: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41

MacromoleculeName: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17.146482 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
AVGIGAVFLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEA QQHLLKLTVW GIKQLQARVL AVERYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALD

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Macromolecule #4: Envelope glycoprotein BG505 SOSIP.664 gp120

MacromoleculeName: Envelope glycoprotein BG505 SOSIP.664 gp120 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 53.864086 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: NLWVTVYYGV PVWKDAETTL FCASDAKAYE TEKHNVWATH ACVPTDPNPQ EIHLENVTEE FNMWKNNMVE QMHTDIISLW DQSLKPCVK LTPLCVTLQC TNVTNNITDD MRGELKNCSF NMTTELRDKK QKVYSLFYRL DVVQINENQG NRSNNSNKEY R LINCNTSA ...String:
NLWVTVYYGV PVWKDAETTL FCASDAKAYE TEKHNVWATH ACVPTDPNPQ EIHLENVTEE FNMWKNNMVE QMHTDIISLW DQSLKPCVK LTPLCVTLQC TNVTNNITDD MRGELKNCSF NMTTELRDKK QKVYSLFYRL DVVQINENQG NRSNNSNKEY R LINCNTSA ITQACPKVSF EPIPIHYCAP AGFAILKCKD KKFNGTGPCP SVSTVQCTHG IKPVVSTQLL LNGSLAEEEV MI RSENITN NAKNILVQFN TPVQINCTRP NNNTRKSIRI GPGQAFYATG DIIGDIRQAH CNVSKATWNE TLGKVVKQLR KHF GNNTII RFANSSGGDL EVTTHSFNCG GEFFYCNTSG LFNSTWISNT SVQGSNSTGS NDSITLPCRI KQIINMWQRI GQAM YAPPI QGVIRCVSNI TGLILTRDGG STNSTTETFR PGGGDMRDNW RSELYKYKVV KIEPLGVAPT RCKRRVVGRR RRRR

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Macromolecule #5: Ab1245 Fab heavy chain

MacromoleculeName: Ab1245 Fab heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 28.154803 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGWSCIILFL VATATGVHSQ VQLQQSGPGL VKPSETLSLT CTVSGGSISE SYYWKWIRQP PGKGLEWVGR IYGSGVSTSY NPSLESRVT ISKDTSKNHF SLKLTSVTAA DTAVYYCARS YVRAETLMFA SLGGPYNRFD VWGAGVLVTV SSASTKGPSV F PLAPSSKS ...String:
MGWSCIILFL VATATGVHSQ VQLQQSGPGL VKPSETLSLT CTVSGGSISE SYYWKWIRQP PGKGLEWVGR IYGSGVSTSY NPSLESRVT ISKDTSKNHF SLKLTSVTAA DTAVYYCARS YVRAETLMFA SLGGPYNRFD VWGAGVLVTV SSASTKGPSV F PLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNS(UNK)ALT SGVHTFPAVL QSS(UNK)LYSLSS VVTVPSSSLG TQTY ICNVN HKPSNTKVDK RVEPKSCDKT HHHHHH

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Macromolecule #6: Ab1245 Fab light chain

MacromoleculeName: Ab1245 Fab light chain / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 25.306172 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGWSCIILFL VATATGSWAQ SALTQPSSAS ASLGASVTLT CTLSSGYSNS AVDWHQQRPG KGPQFVMRVG TGGIVGSKGD GIPDRFSGS GSGLNRYLII KNIQEEDESD YHCGADHGTG SAFVYVFGGG TKLTVLGQPK ASPLVTLFPP SSEELQANKA T LVCLISDF ...String:
MGWSCIILFL VATATGSWAQ SALTQPSSAS ASLGASVTLT CTLSSGYSNS AVDWHQQRPG KGPQFVMRVG TGGIVGSKGD GIPDRFSGS GSGLNRYLII KNIQEEDESD YHCGADHGTG SAFVYVFGGG TKLTVLGQPK ASPLVTLFPP SSEELQANKA T LVCLISDF YPGAVTVAWK ADSSPVKAGV ETTTPSKQSN NKYAASSYLS LTPEQWKSHR SYSCQVTHEG STVEKTVAPT EC S

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Macromolecule #14: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 14 / Number of copies: 23 / 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

Concentration4.7 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
20.0 mMTris-HClTris
150.0 mMsodium chlorideNaClSodium chloride
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Details: 0 blot force, 3 second blot time, 3 uL sample added.
DetailsAb1245 was incubated with BG505 SOSIP at room temperature for 3 hours, after which 8ANC195 Fab was added and the complex was incubated overnight at RT before SEC purification and concentration to 4.7 mg/mL.

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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: 2.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2307 / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 421388
CTF correctionSoftware - Name: Gctf
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 172731
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5cjx


6nc3

chain_id: S

6nc3

chain_id: T
RefinementProtocol: RIGID BODY FIT
Output model

PDB-7mxe:
Ab1245 Fab in complex with BG505 SOSIP.664 and 8ANC195 Fab

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