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- EMDB-26496: Cryo-EM structure of BG24 Fabs with an inferred germline CDRL1 an... -

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Basic information

Entry
Database: EMDB / ID: EMD-26496
TitleCryo-EM structure of BG24 Fabs with an inferred germline CDRL1 and 10-1074 Fabs in complex with HIV-1 Env 6405-SOSIP.664
Map data
Sample
  • Complex: Cryo-EM map of BG24 Fabs with an inferred germline CDRL1 and 10-1074 Fabs in complex with HIV-1 Env 6405-SOSIP.664
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: BG24 with an inferred germline CDRL1 Fab heavy chain
    • Protein or peptide: BG24 with an inferred germline CDRL1 Fab light chain
    • Protein or peptide: 10-1074 Fab heavy chain
    • Protein or peptide: 10-1074 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 / membrane => GO:0016020 / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response ...: / 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 / membrane => GO:0016020 / 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: 3.4 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 9, 2022-
Current statusNov 9, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26496.png

Downloads & links

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Map

FileDownload / File: emd_26496.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: 0.0115
Minimum - Maximum-0.06955855 - 0.11889058
Average (Standard dev.)0.0002699872 (±0.0027791006)
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 the BG24...

Fileemd_26496_additional_1.map
AnnotationLocal refinement map used to build the BG24 with an inferred germline CDRL1 Fab CDRL1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26496_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_26496_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 CDRL1 and 10-1...

EntireName: Cryo-EM map of BG24 Fabs with an inferred germline CDRL1 and 10-1074 Fabs in complex with HIV-1 Env 6405-SOSIP.664
Components
  • Complex: Cryo-EM map of BG24 Fabs with an inferred germline CDRL1 and 10-1074 Fabs in complex with HIV-1 Env 6405-SOSIP.664
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: BG24 with an inferred germline CDRL1 Fab heavy chain
    • Protein or peptide: BG24 with an inferred germline CDRL1 Fab light chain
    • Protein or peptide: 10-1074 Fab heavy chain
    • Protein or peptide: 10-1074 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 CDRL1 and 10-1...

SupramoleculeName: Cryo-EM map of BG24 Fabs with an inferred germline CDRL1 and 10-1074 Fabs in complex with HIV-1 Env 6405-SOSIP.664
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 6405-SOSIP.664 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 50.007793 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NLWVTVYYGV PVWKEAKTTL FCASDAKSYA HNIWATHACV PTDPNPQEVE LVNVTENFNM WKNDMVDQMH EDIISLWDES LKPCVKLTP LCVTLQCSEM KNGTDRMNCS FNATTVVNDK QKKVHALFYR LDIEPIGNNS TEYMLINCNT SAIAQSCPKI T FEPIPIHY ...String:
NLWVTVYYGV PVWKEAKTTL FCASDAKSYA HNIWATHACV PTDPNPQEVE LVNVTENFNM WKNDMVDQMH EDIISLWDES LKPCVKLTP LCVTLQCSEM KNGTDRMNCS FNATTVVNDK QKKVHALFYR LDIEPIGNNS TEYMLINCNT SAIAQSCPKI T FEPIPIHY CAPAGFALLK CRDKQFNGTG PCTNVSSVQC THGIKPVVST QLLLNGSLAE EDIIIRSENL TDNTKTIIVQ LN KSIAINC TRPYNNTRQR IHITNDARVI VGDIRQAHCN VSRVDWNNMT QWAATKLGSL YNRSTIIFNH ASGGDPEITT HSF TCGGEF FYCNTSGLFN STWDIMNTSS PNNTDPIITL QCRIKQIINM WQGVGRAIYA PPIAGQILCS SNITGLLLTR DGGA DNSSH NETFRPGGGN MKDNWRSELY KYKVVKIEPL GVAPTRCKRR VV

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Macromolecule #2: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 2 / Details: Env mimic 6405-SOSIP.664 / 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: BG24 with an inferred germline CDRL1 Fab heavy chain

MacromoleculeName: BG24 with an inferred germline CDRL1 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.758364 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLVQSRAE VKKPGASVKV SCEASGYNFV DHYIHWVRQA PGQAPQWVGW MNPRGGGVAY SQRFQGRVTM TRDTSIDTAY MQLNRLTSG DTAVYYCATQ VKLDSSAGYP FDIWGQGTMV TVSSAS

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Macromolecule #4: BG24 with an inferred germline CDRL1 Fab light chain

MacromoleculeName: BG24 with an inferred germline CDRL1 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.177191 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SALTQPRSVS GSPGQSVNIS CTGTSSDVGG YNYVSWYQQH PGRAPKLIIY EVNRRPSGVS DRFSGSKSGN TASLTISGLR TEDEADYFC SAFEYFGGGT KLTVLS

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Macromolecule #5: 10-1074 Fab heavy chain

MacromoleculeName: 10-1074 Fab heavy chain / type: protein_or_peptide / ID: 5 / 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 #6: 10-1074 Fab light chain

MacromoleculeName: 10-1074 Fab light chain / type: protein_or_peptide / ID: 6 / 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 #12: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 12 / Number of copies: 24 / 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: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 170897
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION

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