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- EMDB-25732: HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-25732
TitleHIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab
Map data
Sample
  • Complex: HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab
    • Protein or peptide: PCT64.LMCA Fab Heavy Chain
    • Protein or peptide: PCT64.LMCA Fab Light Chain
    • Protein or peptide: HIV Envelope ApexGT2.2MUT gp120
    • Protein or peptide: HIV Envelope ApexGT2.2MUT gp41
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHIV / germline targeting vaccine / VIRAL PROTEIN-IMMUNE SYSTEM complex
Biological speciesHuman immunodeficiency virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsBerndsen ZT / Ward AB
Funding support United States, 4 items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationOPP1084519 United States
Bill & Melinda Gates FoundationOPP1196345 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UM1 Al100663 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UM1 AI144462 United States
CitationJournal: Immunity / Year: 2022
Title: Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors.
Authors: Jordan R Willis / Zachary T Berndsen / Krystal M Ma / Jon M Steichen / Torben Schiffner / Elise Landais / Alessia Liguori / Oleksandr Kalyuzhniy / Joel D Allen / Sabyasachi Baboo / ...Authors: Jordan R Willis / Zachary T Berndsen / Krystal M Ma / Jon M Steichen / Torben Schiffner / Elise Landais / Alessia Liguori / Oleksandr Kalyuzhniy / Joel D Allen / Sabyasachi Baboo / Oluwarotimi Omorodion / Jolene K Diedrich / Xiaozhen Hu / Erik Georgeson / Nicole Phelps / Saman Eskandarzadeh / Bettina Groschel / Michael Kubitz / Yumiko Adachi / Tina-Marie Mullin / Nushin B Alavi / Samantha Falcone / Sunny Himansu / Andrea Carfi / Ian A Wilson / John R Yates / James C Paulson / Max Crispin / Andrew B Ward / William R Schief /
Abstract: Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain ...Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development.
History
DepositionDec 14, 2021-
Header (metadata) releaseSep 28, 2022-
Map releaseSep 28, 2022-
UpdateJul 5, 2023-
Current statusJul 5, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_25732.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.689
Minimum - Maximum-4.5300817 - 5.8937945
Average (Standard dev.)0.0014143987 (±0.12018487)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 322.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_25732_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #2

Fileemd_25732_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_25732_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab

EntireName: HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab
Components
  • Complex: HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab
    • Protein or peptide: PCT64.LMCA Fab Heavy Chain
    • Protein or peptide: PCT64.LMCA Fab Light Chain
    • Protein or peptide: HIV Envelope ApexGT2.2MUT gp120
    • Protein or peptide: HIV Envelope ApexGT2.2MUT gp41
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab

SupramoleculeName: HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: PCT64.LMCA Fab Heavy Chain

MacromoleculeName: PCT64.LMCA Fab Heavy Chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.737602 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVKPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVGR IKSKTDGGTT DYAAPVKGRF TISRDDSKNT LYLQMNSLK TEDTAVYYCT TGVETYDFWS G(TYS)DDH(TYS)YDYY FRDVWGKGTT VTVSSASTKG PSVFPLAPSS KST SGGTAA ...String:
EVQLVESGGG LVKPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVGR IKSKTDGGTT DYAAPVKGRF TISRDDSKNT LYLQMNSLK TEDTAVYYCT TGVETYDFWS G(TYS)DDH(TYS)YDYY FRDVWGKGTT VTVSSASTKG PSVFPLAPSS KST SGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKV EPKSC D

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Macromolecule #2: PCT64.LMCA Fab Light Chain

MacromoleculeName: PCT64.LMCA Fab Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.26576 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGSSFTFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGSSFTFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: HIV Envelope ApexGT2.2MUT gp120

MacromoleculeName: HIV Envelope ApexGT2.2MUT gp120 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 56.09398 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGILPSPGMP ALLSLVSLLS VLLMGCVAET GAENLWVTVY YGVPVWKDAE TTLFCASDAK AYETEKHNVW ATHACVPTDP NPQEIHLEN VTEEFNMWKN NMVEQMHEDI ISLWDQSLKP CVKLTPLCVT LQCTNVTNNI TDDMRGELKN CSFNATTELR N KRQKVYSL ...String:
MGILPSPGMP ALLSLVSLLS VLLMGCVAET GAENLWVTVY YGVPVWKDAE TTLFCASDAK AYETEKHNVW ATHACVPTDP NPQEIHLEN VTEEFNMWKN NMVEQMHEDI ISLWDQSLKP CVKLTPLCVT LQCTNVTNNI TDDMRGELKN CSFNATTELR N KRQKVYSL FYRLDIVPMG ENSANYRLID CNTSAITQAC PKVSFEPIPI HYCAPAGFAI LKCKDKKFNG TGPCPSVSTV QC THGIKPV VSTQLLLNGS LAEEEVIIRS ENITNNAKNI LVQLNTPVQI NCTRPNNNTV KSIRIGPGQA FYYTGDIIGD IRQ AHCNVS KATWNETLGK VVKQLRKHFG NNTIIRFAQS SGGDLEVTTH SFNCGGEFFY CNTSGLFNST WISNTSVQGS NSTG SNDSI TLPCRIKQII NMWQRIGQAM YAPPIQGVIR CVSNITGLIL TRDGGSTNST TETFRPGGGD MRDNWRSELY KYKVV KIEP LGVAPTRCKR RVVGRRRRRR

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Macromolecule #4: HIV Envelope ApexGT2.2MUT gp41

MacromoleculeName: HIV Envelope ApexGT2.2MUT gp41 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
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 #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 37 / 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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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: 2.5 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 238078
FSC plot (resolution estimation)

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