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- EMDB-25045: Cytoplasmic tail deleted HIV-1 Env bound with three 4E10 Fabs -

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Basic information

Entry
Database: EMDB / ID: EMD-25045
TitleCytoplasmic tail deleted HIV-1 Env bound with three 4E10 Fabs
Map dataCryo-EM structure of HIV-1 gp145 bound with three 4E10 Fabs
Sample
  • Complex: HIV-1 gp145 bound with three 4E10 Fabs
    • Protein or peptide: 4E10 Fab light chain
    • Protein or peptide: 4E10 Fab heavy chain
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Transmembrane protein gp41Transmembrane protein
  • 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 / virus-mediated perturbation of host defense response / 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 ...: / 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 / membrane => GO:0016020 / 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 / Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHIV whole-genome vector AA1305#18 (others) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.67 Å
AuthorsYang S / Walz T
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nat Commun / Year: 2022
Title: Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack.
Authors: Shuang Yang / Giorgos Hiotis / Yi Wang / Junjian Chen / Jia-Huai Wang / Mikyung Kim / Ellis L Reinherz / Thomas Walz /
Abstract: Vaccines targeting HIV-1's gp160 spike protein are stymied by high viral mutation rates and structural chicanery. gp160's membrane-proximal external region (MPER) is the target of naturally arising ...Vaccines targeting HIV-1's gp160 spike protein are stymied by high viral mutation rates and structural chicanery. gp160's membrane-proximal external region (MPER) is the target of naturally arising broadly neutralizing antibodies (bnAbs), yet MPER-based vaccines fail to generate bnAbs. Here, nanodisc-embedded spike protein was investigated by cryo-electron microscopy and molecular-dynamics simulations, revealing spontaneous ectodomain tilting that creates vulnerability for HIV-1. While each MPER protomer radiates centrally towards the three-fold axis contributing to a membrane-associated tripod structure that is occluded in the upright spike, tilting provides access to the opposing MPER. Structures of spike proteins with bound 4E10 bnAb Fabs reveal that the antibody binds exposed MPER, thereby altering MPER dynamics, modifying average ectodomain tilt, and imposing strain on the viral membrane and the spike's transmembrane segments, resulting in the abrogation of membrane fusion and informing future vaccine development.
History
DepositionSep 29, 2021-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25045.png

Downloads & links

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Map

FileDownload / File: emd_25045.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of HIV-1 gp145 bound with three 4E10 Fabs
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 0.296
Minimum - Maximum-1.062217 - 2.1810966
Average (Standard dev.)0.0007979223 (±0.04024303)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 395.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : HIV-1 gp145 bound with three 4E10 Fabs

EntireName: HIV-1 gp145 bound with three 4E10 Fabs
Components
  • Complex: HIV-1 gp145 bound with three 4E10 Fabs
    • Protein or peptide: 4E10 Fab light chain
    • Protein or peptide: 4E10 Fab heavy chain
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Transmembrane protein gp41Transmembrane protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HIV-1 gp145 bound with three 4E10 Fabs

SupramoleculeName: HIV-1 gp145 bound with three 4E10 Fabs / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: HIV whole-genome vector AA1305#18 (others) / Strain: BG505
Molecular weightTheoretical: 600 KDa

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Macromolecule #1: 4E10 Fab light chain

MacromoleculeName: 4E10 Fab light chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.292705 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVLTQSPGT QSLSPGERAT LSCRASQSVG NNKLAWYQQR PGQAPRLLIY GASSRPSGVA DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGQSLSTF GQGTKVEVKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
EIVLTQSPGT QSLSPGERAT LSCRASQSVG NNKLAWYQQR PGQAPRLLIY GASSRPSGVA DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGQSLSTF GQGTKVEVKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGE

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Macromolecule #2: 4E10 Fab heavy chain

MacromoleculeName: 4E10 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.18025 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGAE VKRPGSSVTV SCKASGGSFS TYALSWVRQA PGRGLEWMGG VIPLLTITNY APRFQGRITI TADRSTSTAY LELNSLRPE DTAVYYCARE GTTGWGWLGK PIGAFAHWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
QVQLVQSGAE VKRPGSSVTV SCKASGGSFS TYALSWVRQA PGRGLEWMGG VIPLLTITNY APRFQGRITI TADRSTSTAY LELNSLRPE DTAVYYCARE GTTGWGWLGK PIGAFAHWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SC

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Macromolecule #3: Envelope glycoprotein gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: HIV whole-genome vector AA1305#18 (others)
Molecular weightTheoretical: 54.064277 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT ...String:
AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT SAITQACPKV SFEPIPIHYC APAGFAILKC KDKKFNGTGP CPSVSTVQCT HGIKPVVSTQ LLLNGSLAEE EV MIRSENI TNNAKNILVQ FNTPVQINCT RPNNNTRKSI RIGPGQAFYA TGDIIGDIRQ AHCNVSKATW NETLGKVVKQ LRK HFGNNT IIRFANSSGG DLEVTTHSFN CGGEFFYCNT SGLFNSTWIS NTSVQGSNST GSNDSITLPC RIKQIINMWQ RIGQ AMYAP PIQGVIRCVS NITGLILTRD GGSTNSTTET FRPGGGDMRD NWRSELYKYK VVKIEPLGVA PTRCKRRVVG RRRRR R

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Macromolecule #4: Transmembrane protein gp41

MacromoleculeName: Transmembrane protein gp41 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: HIV whole-genome vector AA1305#18 (others)
Molecular weightTheoretical: 19.800559 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVGIGAVFLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEA QQHLLKLTVW GIKQLQARVL AVERYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALDKWASLW N WFDISNWL WYIKL

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 36 / 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

Concentration0.2 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 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: 1.5 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 80.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

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

5i8h

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.67 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 362646

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