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- EMDB-26493: Cryo-EM structure of BG24 Fabs with an inferred germline light ch... -

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Basic information

Entry
Database: EMDB / ID: EMD-26493
TitleCryo-EM structure of BG24 Fabs with an inferred germline light chain and 10-1074 Fabs in complex with HIV-1 Env immunogen BG505-SOSIPv4.1-GT1 containing the N276 gp120 glycan- Class 1
Map data
Sample
  • Complex: Cryo-EM map of BG24 Fabs with an inferred germline light chain and 10-1074 Fabs in complex with HIV-1 Env immunogen BG505-SOSIPv4.1-GT1 containing the N276 gp120 glycan- Class 1
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: 10-1074 Fab heavy chain
    • Protein or peptide: BG24 mature Fab heavy chain
    • Protein or peptide: 10-1074 Fab light chain
    • Protein or peptide: BG24 mature Fab light chain
  • 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 / 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 / host cell plasma membrane / virion membrane / structural molecule activity / 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 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsDam KA / 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: Nat Commun / Year: 2022
Title: HIV-1 CD4-binding site germline antibody-Env structures inform vaccine design.
Authors: Kim-Marie A Dam / Christopher O Barnes / Harry B Gristick / Till Schoofs / Priyanthi N P Gnanapragasam / Michel C Nussenzweig / Pamela J Bjorkman /
Abstract: BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4- ...BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24 and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24 variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.
History
DepositionMar 25, 2022-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateNov 16, 2022-
Current statusNov 16, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26493.png

Downloads & links

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Map

FileDownload / File: emd_26493.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.869 Å
Density
Contour LevelBy AUTHOR: 0.0122
Minimum - Maximum-0.017031772 - 0.056561843
Average (Standard dev.)0.0002876393 (±0.002017398)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 312.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local refinement map used to build BG24 LC-iGL Fab CDRL1

Fileemd_26493_additional_1.map
AnnotationLocal refinement map used to build BG24 LC-iGL Fab CDRL1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26493_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26493_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM map of BG24 Fabs with an inferred germline light chain an...

EntireName: Cryo-EM map of BG24 Fabs with an inferred germline light chain and 10-1074 Fabs in complex with HIV-1 Env immunogen BG505-SOSIPv4.1-GT1 containing the N276 gp120 glycan- Class 1
Components
  • Complex: Cryo-EM map of BG24 Fabs with an inferred germline light chain and 10-1074 Fabs in complex with HIV-1 Env immunogen BG505-SOSIPv4.1-GT1 containing the N276 gp120 glycan- Class 1
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: 10-1074 Fab heavy chain
    • Protein or peptide: BG24 mature Fab heavy chain
    • Protein or peptide: 10-1074 Fab light chain
    • Protein or peptide: BG24 mature Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cryo-EM map of BG24 Fabs with an inferred germline light chain an...

SupramoleculeName: Cryo-EM map of BG24 Fabs with an inferred germline light chain and 10-1074 Fabs in complex with HIV-1 Env immunogen BG505-SOSIPv4.1-GT1 containing the N276 gp120 glycan- Class 1
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
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 / Details: Env mimic BG505-SOSIPv4.1-GT1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 49.860875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ENLWVTVYYG VPVWKDAETT LFCASDKKHN VWATHACVPT DPNPQEIHLE NVTEEFNMWK NNMVEQMHTD IISLWDQSLK PCVKLTPLC VTLQCTNVTN NIGELKNCSF NMTTELRDKR QKVHALFYKL DIVPINENQN TSYRLINCNT AAITQACPKV S FEPIPIHY ...String:
ENLWVTVYYG VPVWKDAETT LFCASDKKHN VWATHACVPT DPNPQEIHLE NVTEEFNMWK NNMVEQMHTD IISLWDQSLK PCVKLTPLC VTLQCTNVTN NIGELKNCSF NMTTELRDKR QKVHALFYKL DIVPINENQN TSYRLINCNT AAITQACPKV S FEPIPIHY CAPAGFAILK CKDKKFNGTG PCPSVSTVQC THGIKPVVST QLLLNGSLAE EEVMIRSENI TNNAKNILVQ FN TPVQINC TRPNNNTRKS IRIGPGQWFY ATGDIIGDIR QAHCNVSKAT WNETLGKVVK QLRKHFGNNT IIRFANSSGG DLE VTTHSF NCGGEFFYCD TSGLFNSTWI SNDSITLPCR IKQIINMWQR IGQAMYAPPI QGVIRCVSNI TGLILTRDGG STDS TTETF RPSGGDMRDN WRSELYKYKV VKIEPLGVAP TRCKRRVV

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Macromolecule #2: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 2 / Details: Env mimic BG505-SOSIPv4.1-GT1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 14.577591 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
FLGFLGAAGS TMGAASMTLT VQARNLLSLL KLTVWGIKQL QARVLAVERY LRDQQLLGIW GCSGKLICCT NVPWNSSWSN RNLSEIWDN MTWLQWDKEI SNYTQIIYGL LEESQNQQEK NEQDLLALD

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Macromolecule #3: 10-1074 Fab heavy chain

MacromoleculeName: 10-1074 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.791433 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLQESGPG LVKPSETLSV TCSVSGDSMN NYYWTWIRQS PGKGLEWIGY ISDRESATYN PSLNSRVVIS RDTSKNQLSL KLNSVTPAD TAVYYCATAR RGQRIYGVVS FGEFFYYYSM DVWGKGTTVT VSSA

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Macromolecule #4: BG24 mature Fab heavy chain

MacromoleculeName: BG24 mature Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.384042 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VQLVQSRAEV KKPGASVKVS CEASGYNFVD HYIHWVRQAP GQRPQWVGWM NPRGGGVAYS QRFQGRVTMT RDTSIDTAYM QLNRLTSGD TAVYYCATQV KLDSSAGYPF DIWGQGTMVT V

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Macromolecule #5: 10-1074 Fab light chain

MacromoleculeName: 10-1074 Fab light chain / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.701023 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VRPLSVALGE TARISCGRQA LGSRAVQWYQ HRPGQAPILL IYNNQDRPSG IPERFSGTPD INFGTRATLT ISGVEAGDEA DYYCHMWDS RSGFSWSFGG ATRLTVLG

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Macromolecule #6: BG24 mature Fab light chain

MacromoleculeName: BG24 mature Fab light chain / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.084096 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SALTQPRSVS GSPGQSVTIS CTGTSSDVGG YNYVSWYQQH PGKAPKLMIY DVSKRPSGVP DRFSGSKSGN TASLTISGLQ AEDEADYYC SSYEYFGGGT KLTVLS

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Macromolecule #10: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 10 / Number of copies: 33 / 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

BufferpH: 8
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5cez


Details: Closed conformation Env trimer (gp120/gp41 subunits) low-pass filtered to 80 angstrom
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 23830
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION

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