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- EMDB-44482: Cryo-EM structure of the HIV-1 JR-FL IDL Env trimer in complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-44482
TitleCryo-EM structure of the HIV-1 JR-FL IDL Env trimer in complex with PGT122 Fab
Map datasharpened map
Sample
  • Complex: Cryo-EM Structure of the HIV-1 JR-FL IDL Env trimer in complex with PGT122 Fab
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: PGT122 heavy chain
    • Protein or peptide: PGT122 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: SULFATE ION
KeywordsCD4 / HIV-1 / SOSIP / Vaccine / gp120 / gp41 / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 / 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 ...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 / 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 / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / identical protein binding / 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 speciesHuman immunodeficiency virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 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_44482.png

Downloads & links

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Map

FileDownload / File: emd_44482.map.gz / Format: CCP4 / Size: 125 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 320 pix.
= 343.456 Å		1.07 Å/pix.
x 320 pix.
= 343.456 Å		1.07 Å/pix.
x 320 pix.
= 343.456 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: 0.12
Minimum - Maximum-0.07422493 - 0.4303507
Average (Standard dev.)0.0036620242 (±0.020205604)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 343.456 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44482_msk_1.map
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Additional map: unsharpened map

Fileemd_44482_additional_1.map
Annotationunsharpened map
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Additional map: resolve map

Fileemd_44482_additional_2.map
Annotationresolve map
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Half map: half map B

Fileemd_44482_half_map_1.map
Annotationhalf map B
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Half map: half map A

Fileemd_44482_half_map_2.map
Annotationhalf map A
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Sample components

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Entire : Cryo-EM Structure of the HIV-1 JR-FL IDL Env trimer in complex wi...

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

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Supramolecule #1: Cryo-EM Structure of the HIV-1 JR-FL IDL Env trimer in complex wi...

SupramoleculeName: Cryo-EM Structure of the HIV-1 JR-FL 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 gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 53.686918 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VEKLWVTVYY GVPVWKEATT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLENVT EHFNMWKNNM VEQMQEDIIS LWCQSLKPC VKLTPLCVTL NCKDVNATNT TNDSEGTMER GEIKNCSFNI TTSIRDKVQK EYALFYKLDV VPIDNNNTSY R LISCNTSV ...String:
VEKLWVTVYY GVPVWKEATT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLENVT EHFNMWKNNM VEQMQEDIIS LWCQSLKPC VKLTPLCVTL NCKDVNATNT TNDSEGTMER GEIKNCSFNI TTSIRDKVQK EYALFYKLDV VPIDNNNTSY R LISCNTSV ITQACPKISF EPIPIHYCAP AGFAILKCND KTFNGTGPCK NVSTVQCTHG IRPVVSTQLL LNGSLAEEEV VI RSDNFTN NAKTIIVQLK ESVEINCTRP NNNTRKSIHI GPGRAFYTTG EIIGDIRQAH CNISRAKWND TLKQIVIKLR EQF ENKTIV FNHSSGGDPE IVMHSFNCGG EFFYCNSTQL FNSTWNNNTE GSNNTEGNTI TLPCRIKQII NMWQEVGGCG AMYA PPIRG QIRCSSNITG LLLTRDGGIN ENGTEIFRPG GGDMRDNWRS ELYKYKVVKI EPLGVAPTKA KRRVVGRRRR RR

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #2: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17.227549 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVGIGAVFLG FLGAAGSTMG AASMTLTVQA RLLLSGIVQQ QNNLLRAPEA QQRMLQLTVW GIKQLQARVL AVERYLGDQQ LLGIWGCSG KLICTTAVPW NASWSNKSLD RIWNNMTWME WEREIDNYTS EIYTLIEESQ NQQEKNEQEL LELD

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: SULFATE ION

MacromoleculeName: SULFATE ION / type: ligand / ID: 9 / Number of copies: 1 / Formula: SO4
Molecular weightTheoretical: 96.063 Da
Chemical component information

ChemComp-SO4:
SULFATE 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

Concentration1.0 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: C-flat-1.2/1.3 / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
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: 70.73 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: 4.0 µm / Nominal defocus min: 0.4 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: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.14) / Number images used: 31576
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 modelPDB ID:

5fuu


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9ber:
Cryo-EM structure of the HIV-1 JR-FL IDL Env trimer in complex with PGT122 Fab

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