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- EMDB-23861: Asymmetric structure of the uncleaved full-length HIV-1 envelope ... -

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Basic information

Entry
Database: EMDB / ID: EMD-23861
TitleAsymmetric structure of the uncleaved full-length HIV-1 envelope glycoprotein trimer in state U2
Map data
Sample
  • Complex: The uncleaved full-length human immunodeficiency virus (HIV-1) envelope glycoprotein trimer
    • Protein or peptide: HIV-1 gp160 glycoprotein
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
Similarity search - Component
Biological speciesHIV-1 (virus)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.7 Å
AuthorsZhang SJ / Wang KY / Wang WL / Sodroksi J / Mao YD
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)11774012 China
CitationJournal: J Virol / Year: 2021
Title: Asymmetric Structures and Conformational Plasticity of the Uncleaved Full-Length Human Immunodeficiency Virus Envelope Glycoprotein Trimer.
Authors: Shijian Zhang / Kunyu Wang / Wei Li Wang / Hanh T Nguyen / Shuobing Chen / Maolin Lu / Eden P Go / Haitao Ding / Robert T Steinbock / Heather Desaire / John C Kappes / Joseph Sodroski / Youdong Mao /
Abstract: The functional human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)] is produced by cleavage of a conformationally flexible gp160 precursor. gp160 cleavage or the ...The functional human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)] is produced by cleavage of a conformationally flexible gp160 precursor. gp160 cleavage or the binding of BMS-806, an entry inhibitor, stabilizes the pretriggered, "closed" (state 1) conformation recognized by rarely elicited broadly neutralizing antibodies. Poorly neutralizing antibodies (pNAbs) elicited at high titers during natural infection recognize more "open" Env conformations (states 2 and 3) induced by binding the receptor, CD4. We found that BMS-806 treatment and cross-linking decreased the exposure of pNAb epitopes on cell surface gp160; however, after detergent solubilization, cross-linked and BMS-806-treated gp160 sampled non-state-1 conformations that could be recognized by pNAbs. Cryo-electron microscopy of the purified BMS-806-bound gp160 revealed two hitherto unknown asymmetric trimer conformations, providing insights into the allosteric coupling between trimer opening and structural variation in the gp41 HR1 region. The individual protomer structures in the asymmetric gp160 trimers resemble those of other genetically modified or antibody-bound cleaved HIV-1 Env trimers, which have been suggested to assume state-2-like conformations. Asymmetry of the uncleaved Env potentially exposes surfaces of the trimer to pNAbs. To evaluate the effect of stabilizing a state-1-like conformation of the membrane Env precursor, we treated cells expressing wild-type HIV-1 Env with BMS-806. BMS-806 treatment decreased both gp160 cleavage and the addition of complex glycans, implying that gp160 conformational flexibility contributes to the efficiency of these processes. Selective pressure to maintain flexibility in the precursor of functional Env allows the uncleaved Env to sample asymmetric conformations that potentially skew host antibody responses toward pNAbs. The envelope glycoprotein (Env) trimers on the surface of human immunodeficiency virus (HIV-1) mediate the entry of the virus into host cells and serve as targets for neutralizing antibodies. The functional Env trimer is produced by cleavage of the gp160 precursor in the infected cell. We found that the HIV-1 Env precursor is highly plastic, allowing it to assume different asymmetric shapes. This conformational plasticity is potentially important for Env cleavage and proper modification by sugars. Having a flexible, asymmetric Env precursor that can misdirect host antibody responses without compromising virus infectivity would be an advantage for a persistent virus like HIV-1.
History
DepositionApr 17, 2021-
Header (metadata) releaseSep 22, 2021-
Map releaseSep 22, 2021-
UpdateDec 8, 2021-
Current statusDec 8, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7n6w
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23861.png

Downloads & links

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Map

FileDownload / File: emd_23861.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.69 Å/pix.
x 336 pix.
= 230.16 Å		0.69 Å/pix.
x 336 pix.
= 230.16 Å		0.69 Å/pix.
x 336 pix.
= 230.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.685 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01 / Movie #1: 0.01
Minimum - Maximum-0.010870146 - 0.032141186
Average (Standard dev.)2.487735e-05 (±0.0020210743)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 230.16 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.6850.6850.685
M x/y/z336336336
origin x/y/z0.0000.0000.000
length x/y/z230.160230.160230.160
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS336336336
D min/max/mean-0.0110.0320.000

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Supplemental data

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Sample components

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Entire : The uncleaved full-length human immunodeficiency virus (HIV-1) en...

EntireName: The uncleaved full-length human immunodeficiency virus (HIV-1) envelope glycoprotein trimer
Components
  • Complex: The uncleaved full-length human immunodeficiency virus (HIV-1) envelope glycoprotein trimer
    • Protein or peptide: HIV-1 gp160 glycoprotein

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Supramolecule #1: The uncleaved full-length human immunodeficiency virus (HIV-1) en...

SupramoleculeName: The uncleaved full-length human immunodeficiency virus (HIV-1) envelope glycoprotein trimer
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: HIV-1 (virus)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Macromolecule #1: HIV-1 gp160 glycoprotein

MacromoleculeName: HIV-1 gp160 glycoprotein / type: protein_or_peptide / ID: 1 / Enantiomer: DEXTRO
SequenceString: MRVKEKYQHL WRWGWRWGTM LLGMLMICSA TEKLWVTVYY GVPVWKEATT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLENVT EHFNMWKNNM VEQMQEDIIS LWDQSLKPCV KLTPLCVTLN CKDVNATNTT NDSEGTMERG EIKNCSFNIT TSIRDEVQKE ...String:
MRVKEKYQHL WRWGWRWGTM LLGMLMICSA TEKLWVTVYY GVPVWKEATT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLENVT EHFNMWKNNM VEQMQEDIIS LWDQSLKPCV KLTPLCVTLN CKDVNATNTT NDSEGTMERG EIKNCSFNIT TSIRDEVQKE YALFYKLDVV PIDNNNTSYR LISCDTSVIT QACPKISFEP IPIHYCAPAG FAILKCNDKT FNGKGPCKNV STVQCTHGIR PVVSTQLLLN GSLAEEEVVI RSDNFTNNAK TIIVQLKESV EINCTRPNNN TRKSIHIGPG RAFYTTGEII GDIRQAHCNI SRAKWNDTLK QIVIKLREQF ENKTIVFNHS SGGDPEIVMH SFNCGGEFFY CNSTQLFNST WNNNTEGSNN TEGNTITLPC RIKQIINMWQ EVGKAMYAPP IRGQIRCSSN ITGLLLTRDG GINENGTEIF RPGGGDMRDN WRSELYKYKV VKIEPLGVAP TKAKRRVVQS EKSAVGIGAV FLGFLGAAGS TMGAASMTLT VQARLLLSGI VQQQNNLLRA IEAQQRMLQL TVWGIKQLQA RVLAVERYLG DQQLLGIWGC SGKLICTTAV PWNASWSNKS LDRIWNNMTW MEWEREIDNY TSEIYTLIEE SQNQQEKNEQ ELLELDKWAS LWNWFDITKW LWYIKIFIMI VGGLVGLRLV FTVLSIVNRV RQGYSPLSFQ TLLPAPRGPD RPEGIEEEGG ERDRDRSGRL VNGSLALIWD DLRSLCLFSY HRLRDLLLIV TRIVELLGRR GWEALKYWWN LLQYWSQELK NSAVSLLNAT AIAVAEGTDR VIEVVQGACR AIRHIPRRIR QGLERILL

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 55571
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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