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- EMDB-44491: Cryo-EM structure of the HIV-1 WITO IDL Env trimer in complex wit... -

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Basic information

Entry
Database: EMDB / ID: EMD-44491
TitleCryo-EM structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab
Map datasharpened map
Sample
  • Complex: Cryo-EM Structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: PGT122 heavy chain
    • Protein or peptide: PGT122 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: PHOSPHATE ION
KeywordsCD4 / HIV-1 / SOSIP / Vaccine / gp120 / gp41 / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


virus-mediated perturbation of host defense response => GO:0019049 / : / 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 => GO:0019049 / : / 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 / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / 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: 4.5 Å
AuthorsGorman J / Kwong PD
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
Simons FoundationSF349247 United States
CitationJournal: Cell Rep / Year: 2024
Title: Design of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation.
Authors: Peng Zhang / Jason Gorman / Yaroslav Tsybovsky / Maolin Lu / Qingbo Liu / Vinay Gopan / Mamta Singh / Yin Lin / Huiyi Miao / Yuna Seo / Alice Kwon / Adam S Olia / Gwo-Yu Chuang / Hui Geng / ...Authors: Peng Zhang / Jason Gorman / Yaroslav Tsybovsky / Maolin Lu / Qingbo Liu / Vinay Gopan / Mamta Singh / Yin Lin / Huiyi Miao / Yuna Seo / Alice Kwon / Adam S Olia / Gwo-Yu Chuang / Hui Geng / Yen-Ting Lai / Tongqing Zhou / John R Mascola / Walther Mothes / Peter D Kwong / Paolo Lusso /
Abstract: Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature ...Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature between gp120 and gp41 constrains intersubunit mobility and may alter antigenicity. Here, we report an alternative strategy to generate stabilized soluble Env trimers free of covalent gp120-gp41 bonds. Stabilization was achieved by introducing an intrasubunit disulfide bond between the inner and outer domains of gp120, defined as interdomain lock (IDL). Correctly folded IDL trimers displaying a native-like antigenic profile were produced for HIV-1 Envs of different clades. Importantly, the IDL design abrogated CD4 binding while not affecting recognition by potent neutralizing antibodies to the CD4-binding site. By cryoelectron microscopy, IDL trimers were shown to adopt a closed prefusion configuration, while single-molecule fluorescence resonance energy transfer documented a high prevalence of native-like conformation. Thus, IDL trimers may be promising candidates as vaccine immunogens.
History
DepositionApr 16, 2024-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateJul 31, 2024-
Current statusJul 31, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44491.png

Downloads & links

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Map

FileDownload / File: emd_44491.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 352 pix.
= 377.802 Å		1.07 Å/pix.
x 352 pix.
= 377.802 Å		1.07 Å/pix.
x 352 pix.
= 377.802 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0733 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-0.19691625 - 1.2985365
Average (Standard dev.)0.008670217 (±0.056057133)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 377.8016 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44491_msk_1.map
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Additional map: unsharpened map

Fileemd_44491_additional_1.map
Annotationunsharpened map
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Additional map: resolve map

Fileemd_44491_additional_2.map
Annotationresolve map
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Half map: half map A

Fileemd_44491_half_map_1.map
Annotationhalf map A
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Half map: half map B

Fileemd_44491_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Cryo-EM Structure of the HIV-1 WITO IDL Env trimer in complex wit...

EntireName: Cryo-EM Structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab
Components
  • Complex: Cryo-EM Structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: PGT122 heavy chain
    • Protein or peptide: PGT122 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: PHOSPHATE ION

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Supramolecule #1: Cryo-EM Structure of the HIV-1 WITO IDL Env trimer in complex wit...

SupramoleculeName: Cryo-EM Structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17.381771 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVTLGAVFLG FLGAAGSTMG AASLTLTVQA RLLLSGIVQQ QSNLLRAPEA QQHMLQLTVW GIKQLQARVL AIERYLKDQQ LLGIWGCSG KLICTTTVPW NTSWSNKSYD YIWNNMTWMQ WEREIDNYTG FIYTLIEESQ NQQEKNELEL LELD

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #2: Envelope glycoprotein gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 53.827133 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AEQLWVTVYY GVPVWREANT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVMGNVT EDFNMWKNNM VEQMHEDIIS LWCQSLKPC VKLTPLCVTL HCTNVTISST NGSTANVTMR EEMKNCSFNT TTVIRDKIQK EYALFYKLDI VPIEGKNTNT S YRLINCNT ...String:
AEQLWVTVYY GVPVWREANT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVMGNVT EDFNMWKNNM VEQMHEDIIS LWCQSLKPC VKLTPLCVTL HCTNVTISST NGSTANVTMR EEMKNCSFNT TTVIRDKIQK EYALFYKLDI VPIEGKNTNT S YRLINCNT SVITQACPKV SFEPIPIHYC APAGFAILKC NNKTFNGKGP CRNVSTVQCT HGIKPVVSTQ LLLNGSLAEE DI IIRSENF TNNGKNIIVQ LKEPVKINCT RPGNNTRRSI NIGPGRAFYA TGAIIGDIRK AHCNISTEQW NNTLTQIVDK LRE QFGN(UNK)K TIIFNQSSGG DPEVVMHTFN CGGEFFYCNS TQLFNSTWFN NGTSTWNSTA DNITLPCRIK QVINMWQEVG GCGAMYAPP IRGQIDCSSN ITGLILTRDG GSNSSQNETF RPGGGNMKDN WRSELYKYKV VKIEPLGIAP TRAKRRVVQR R RRRR

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #3: PGT122 heavy chain

MacromoleculeName: PGT122 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.838731 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVHLQESGPG LVKPSETLSL TCNVSGTLVR DNYWSWIRQP LGKQPEWIGY VHDSGDTNYN PSLKSRVHLS LDKSKNLVSL RLTGVTAAD SAIYYCATTK HGRRIYGVVA FKEWFTYFYM DVWGKGTSVT VSS

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Macromolecule #4: PGT122 light chain

MacromoleculeName: PGT122 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.423534 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
TFVSVAPGQT ARITCGEESL GSRSVIWYQQ RPGQAPSLII YNNNDRPSGI PDRFSGSPGS TFGTTATLTI TSVEAGDEAD YYCHIWDSR RPTNWVFGEG TTLIVL

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 45 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #9: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 9 / Number of copies: 1 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION

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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

Concentration2 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: C-flat-1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average exposure time: 10.0 sec. / Average electron dose: 70.77 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.7 µm / Nominal defocus min: 0.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.14) / Number images used: 12615
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 2.12)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9bf6:
Cryo-EM structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab

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