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- EMDB-26492: Cryo-EM structure of BG24 inferred germline Fabs with mature CDR3... -

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Basic information

Entry
Database: EMDB / ID: EMD-26492
TitleCryo-EM structure of BG24 inferred germline Fabs with mature CDR3s and 10-1074 Fabs in complex with HIV-1 Env immunogen BG505-SOSIPv4.1-GT1
Map data
Sample
  • Complex: Cryo-EM map of BG24-iGL CDR3mat and 10-1074 Fabs in complex with BG505 SOSIP.664v4.1-GT1 Env trimer immunogen
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: 10-1074 Fab heavy chain
    • Protein or peptide: 10-1074 Fab light chain
    • Protein or peptide: BG24 inferred germline Fab with mature CDR3s heavy chain
    • Protein or peptide: BG24 inferred germline Fab with mature CDR3s light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: alpha-D-mannopyranose
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 / 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: 4.1 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) releaseOct 26, 2022-
Map releaseOct 26, 2022-
UpdateOct 26, 2022-
Current statusOct 26, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26492.png

Downloads & links

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Map

FileDownload / File: emd_26492.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.14 Å
Density
Contour LevelBy AUTHOR: 0.0223
Minimum - Maximum-0.14641865 - 0.24396893
Average (Standard dev.)0.00045641602 (±0.006114014)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 291.84 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-iGL CDR3mat Fab CDRL1

Fileemd_26492_additional_1.map
AnnotationLocal refinement map used to build BG24-iGL CDR3mat Fab CDRL1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26492_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_26492_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-iGL CDR3mat and 10-1074 Fabs in complex with ...

EntireName: Cryo-EM map of BG24-iGL CDR3mat and 10-1074 Fabs in complex with BG505 SOSIP.664v4.1-GT1 Env trimer immunogen
Components
  • Complex: Cryo-EM map of BG24-iGL CDR3mat and 10-1074 Fabs in complex with BG505 SOSIP.664v4.1-GT1 Env trimer immunogen
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: 10-1074 Fab heavy chain
    • Protein or peptide: 10-1074 Fab light chain
    • Protein or peptide: BG24 inferred germline Fab with mature CDR3s heavy chain
    • Protein or peptide: BG24 inferred germline Fab with mature CDR3s light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: alpha-D-mannopyranose

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Supramolecule #1: Cryo-EM map of BG24-iGL CDR3mat and 10-1074 Fabs in complex with ...

SupramoleculeName: Cryo-EM map of BG24-iGL CDR3mat and 10-1074 Fabs in complex with BG505 SOSIP.664v4.1-GT1 Env trimer immunogen
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: 52.322422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ENLWVTVYYG VPVWKDAETT LFCASDAKAY ETKKHNVWAT HACVPTDPNP QEIHLENVTE EFNMWKNNMV EQMHTDIISL WDQSLKPCV KLTPLCVTLQ CTNVTNNITD DMRGELKNCS FNMTTELRDK RQKVHALFYK LDIVPINENQ NTSYRLINCN T AAITQACP ...String:
ENLWVTVYYG VPVWKDAETT LFCASDAKAY ETKKHNVWAT HACVPTDPNP QEIHLENVTE EFNMWKNNMV EQMHTDIISL WDQSLKPCV KLTPLCVTLQ CTNVTNNITD DMRGELKNCS FNMTTELRDK RQKVHALFYK LDIVPINENQ NTSYRLINCN T AAITQACP KVSFEPIPIH YCAPAGFAIL KCKDKKFNGT GPCPSVSTVQ CTHGIKPVVS TQLLLNGSLA EEEVMIRSED IR NNAKNIL VQFNTPVQIN CTRPNNNTRK SIRIGPGQWF YATGDIIGDI RQAHCNVSKA TWNETLGKVV KQLRKHFGNN TII RFANSS GGDLEVTTHS FNCGGEFFYC DTSGLFNSTW ISNTSVQGSN STGSNDSITL PCRIKQIINM WQRIGQAMYA PPIQ GVIRC VSNITGLILT RDGGSTDSTT ETFRPSGGDM RDNWRSELYK YKVVKIEPLG VAPTRCKRRV V

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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: 14.676723 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VFLGFLGAAG STMGAASMTL TVQARNLLSL LKLTVWGIKQ LQARVLAVER YLRDQQLLGI WGCSGKLICC TNVPWNSSWS NRNLSEIWD NMTWLQWDKE ISNYTQIIYG LLEESQNQQE KNEQDLLALD

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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: 10-1074 Fab light chain

MacromoleculeName: 10-1074 Fab light chain / type: protein_or_peptide / ID: 4 / 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 #5: BG24 inferred germline Fab with mature CDR3s heavy chain

MacromoleculeName: BG24 inferred germline Fab with mature CDR3s heavy chain
type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.697314 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTNY AQKFQGRVTM TRDTSISTAY MELSRLRSD DTAVYYCATQ VKLDSSAGYP FDIWGQGTMV TVSSAS

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Macromolecule #6: BG24 inferred germline Fab with mature CDR3s light chain

MacromoleculeName: BG24 inferred germline Fab with mature CDR3s light chain
type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.180226 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSALTQPRSV SGSPGQSVTI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVSKRPSGV PDRFSGSKSG NTASLTISGL QAEDEADYY CSAFEYFGGG TKLTVLS

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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: 21 / 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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Macromolecule #15: alpha-D-mannopyranose

MacromoleculeName: alpha-D-mannopyranose / type: ligand / ID: 15 / Number of copies: 4 / Formula: MAN
Molecular weightTheoretical: 180.156 Da
Chemical component information

ChemComp-MAN:
alpha-D-mannopyranose / Mannose

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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
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 60.0 e/Å2
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
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 225140

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