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- EMDB-28941: HIV Env BG505_MD39_B11 SOSIP boosting trimer in complex with B11_... -

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Entry
Database: EMDB / ID: EMD-28941
TitleHIV Env BG505_MD39_B11 SOSIP boosting trimer in complex with B11_d77.7 mouse Fab and RM20A3 Fab
Map datasharpened map
Sample
  • Complex: HIV-1 Env BG505_MD39_B11 SOSIP in complex with Fabs B11_d77.7 and RM20A3
    • Protein or peptide: BG505_MD39_B11 gp120
    • Protein or peptide: RM20A3 Fab heavy chain
    • Protein or peptide: RM20A3 Fab light chain
    • Protein or peptide: BG505_MD39_B11 gp41
    • Protein or peptide: B11_d77.7 Fab heavy chain
    • Protein or peptide: B11_d77.7 Fab kappa light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsmouse antibody / germline targeting / HIV-1 / vaccine design / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Biological speciesHuman immunodeficiency virus / Macaca mulatta (Rhesus monkey) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsTorres JL / Ozorowski G / Ward AB
Funding support United States, 2 items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationOPP1115782/INV-002916 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UMI A1144462 United States
CitationJournal: Science / Year: 2024
Title: mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies.
Authors: Zhenfei Xie / Ying-Cing Lin / Jon M Steichen / Gabriel Ozorowski / Sven Kratochvil / Rashmi Ray / Jonathan L Torres / Alessia Liguori / Oleksandr Kalyuzhniy / Xuesong Wang / John E Warner / ...Authors: Zhenfei Xie / Ying-Cing Lin / Jon M Steichen / Gabriel Ozorowski / Sven Kratochvil / Rashmi Ray / Jonathan L Torres / Alessia Liguori / Oleksandr Kalyuzhniy / Xuesong Wang / John E Warner / Stephanie R Weldon / Gordon A Dale / Kathrin H Kirsch / Usha Nair / Sabyasachi Baboo / Erik Georgeson / Yumiko Adachi / Michael Kubitz / Abigail M Jackson / Sara T Richey / Reid M Volk / Jeong Hyun Lee / Jolene K Diedrich / Thavaleak Prum / Samantha Falcone / Sunny Himansu / Andrea Carfi / John R Yates / James C Paulson / Devin Sok / Andrew B Ward / William R Schief / Facundo D Batista /
Abstract: Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells ...Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody-induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan-targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.
History
DepositionNov 23, 2022-
Header (metadata) releaseMay 15, 2024-
Map releaseMay 15, 2024-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28941.png

Downloads & links

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Map

FileDownload / File: emd_28941.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.209448 - 2.2102394
Average (Standard dev.)-0.00024286553 (±0.037233464)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 478.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28941_msk_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: half map B

Fileemd_28941_half_map_1.map
Annotationhalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_28941_half_map_2.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : HIV-1 Env BG505_MD39_B11 SOSIP in complex with Fabs B11_d77.7 and...

EntireName: HIV-1 Env BG505_MD39_B11 SOSIP in complex with Fabs B11_d77.7 and RM20A3
Components
  • Complex: HIV-1 Env BG505_MD39_B11 SOSIP in complex with Fabs B11_d77.7 and RM20A3
    • Protein or peptide: BG505_MD39_B11 gp120
    • Protein or peptide: RM20A3 Fab heavy chain
    • Protein or peptide: RM20A3 Fab light chain
    • Protein or peptide: BG505_MD39_B11 gp41
    • Protein or peptide: B11_d77.7 Fab heavy chain
    • Protein or peptide: B11_d77.7 Fab kappa light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HIV-1 Env BG505_MD39_B11 SOSIP in complex with Fabs B11_d77.7 and...

SupramoleculeName: HIV-1 Env BG505_MD39_B11 SOSIP in complex with Fabs B11_d77.7 and RM20A3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6

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Macromolecule #1: BG505_MD39_B11 gp120

MacromoleculeName: BG505_MD39_B11 gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus
Molecular weightTheoretical: 54.126512 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHEDIIS LWDQSLKPC VKLTPLCVTL QCTNYTPNLT SMMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT ...String:
AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHEDIIS LWDQSLKPC VKLTPLCVTL QCTNYTPNLT SMMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT SAITQACPKV SFEPIPIHYC APAGFAILKC KDKKFNGTGP CPSVSTVQCT HGIKPVVSTQ LLLNGSLAEE EV IIRSENI TNNAKNILVQ LNTPVQINCT RPNNNTVKSI RIGPGQAFYY TGDIIGDIRM AHCNVSKATW NETLGKVVKQ LRK HFGNNT IIRFAQSSGG DLEVTTHSFN CGGEFFYCNT SGLFNSTWIS NTSVQGSNST GSNDSITLPC RIKQIINMWQ RIGQ AMYAP PIQGVIRCVS NITGLILTRD GGSTNSTTET FRPGGGDMRD NWRSELYKYK VVKIEPLGVA PTRCKRRVVG RRRRR R

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Macromolecule #2: RM20A3 Fab heavy chain

MacromoleculeName: RM20A3 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
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 Fab light chain

MacromoleculeName: RM20A3 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 13.5088 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ALTQPPSVSG SPGQSVTISC TGTSSDIGSY NYVSWYQQHP GKAPKLMIYD VTQRPSGVSD RFSGSKSGNT ASLTISGLQA DDEADYYCS AYAGRQTFYI FGGGTRLTVL GQPKASPTVT LFPPSSEEL

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Macromolecule #4: BG505_MD39_B11 gp41

MacromoleculeName: BG505_MD39_B11 gp41 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus
Molecular weightTheoretical: 18.250541 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVGIGAVSLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEP QQHLLKDTHW GIKQLQARVL AVEHYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALDGTKHHH H HH

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Macromolecule #5: B11_d77.7 Fab heavy chain

MacromoleculeName: B11_d77.7 Fab heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 14.061645 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLQESGPG LVQPSGTLSL TCAVSGDSIS SNNWWTWVRQ PPGKGLEWIG EIYQSGITKY NPSLKSRVST SVDKSKNQFS LRLSSVTAA DTAVYYCARS AISIFGVVVL GEYYYNGMDV WGQGTTVTVS S

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Macromolecule #6: B11_d77.7 Fab kappa light chain

MacromoleculeName: B11_d77.7 Fab kappa light chain / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.76193 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIQMTQSPAS QSVSVGETVT ITCRVSENIY SHLAWYQQKQ GKSPQLLVYG ATNLADGVPS RFSGSGSGTQ YSLKINNLQS EDFGSYYCQ HFWDAPYTFG GGTKLEIK

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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: 45 / 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

Concentration5.9 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / 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 / Details: 5-6 s blot time.

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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 / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average exposure time: 9.8 sec. / Average electron dose: 50.7 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: cryosparc ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2) / Number images used: 129821
FSC plot (resolution estimation)

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