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- EMDB-23462: Structure of CD4 mimetic BNM-III-170 in complex with BG505 SOSIP.... -

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Basic information

Entry
Database: EMDB / ID: EMD-23462
TitleStructure of CD4 mimetic BNM-III-170 in complex with BG505 SOSIP.664 HIV-1 Env trimer and 17b Fab
Map data
SampleComplex of BG505 SOSIP.664 Env with CD4 mimetic BNM-III-170 and 17b Fab
  • 17b Fab
  • BG505 SOSIP.664 HIV-1 Env trimer
  • Envelope glycoprotein BG505 SOSIP.664 gp120
  • HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
  • 17b Fab Light Chain
  • 17b Fab Heavy Chain
  • (ligand) x 2
Function / homology
Function and homology information


positive regulation of plasma membrane raft polarization / positive regulation of establishment of T cell polarity / positive regulation of receptor clustering / actin filament reorganization / host cell endosome membrane / mitigation of host immune response by virus / clathrin-dependent endocytosis of virus by host cell / fusion of virus membrane with host plasma membrane / viral protein processing / fusion of virus membrane with host endosome membrane ...positive regulation of plasma membrane raft polarization / positive regulation of establishment of T cell polarity / positive regulation of receptor clustering / actin filament reorganization / host cell endosome membrane / mitigation of host immune response by virus / clathrin-dependent endocytosis of virus by host cell / fusion of virus membrane with host plasma membrane / viral protein processing / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / integral component of membrane / identical protein binding / plasma membrane
Retroviral envelope protein GP41-like / Envelope glycoprotein Gp160 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / Gp120 core superfamily
Envelope glycoprotein gp160
Biological speciesHomo sapiens (human) / Human immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsJette CA / Bjorkman PJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)2 P50 AI150464 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HIVRAD P01 AI100148 United States
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation.
Authors: Claudia A Jette / Christopher O Barnes / Sharon M Kirk / Bruno Melillo / Amos B Smith / Pamela J Bjorkman /
Abstract: Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host ...Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host receptor CD4, which triggers conformational changes allowing binding to a coreceptor and subsequent membrane fusion. Small molecule or peptide CD4-mimetic drugs mimic CD4's Phe43 interaction with Env by inserting into the conserved Phe43 pocket on Env subunit gp120. Here, we present single-particle cryo-EM structures of CD4-mimetics BNM-III-170 and M48U1 bound to a BG505 native-like Env trimer plus the CD4-induced antibody 17b at 3.7 Å and 3.9 Å resolution, respectively. CD4-mimetic-bound BG505 exhibits canonical CD4-induced conformational changes including trimer opening, formation of the 4-stranded gp120 bridging sheet, displacement of the V1V2 loop, and formation of a compact and elongated gp41 HR1C helical bundle. We conclude that CD4-induced structural changes on both gp120 and gp41 Env subunits are induced by binding to the gp120 Phe43 pocket.
Validation ReportSummary, Full report, XML, About validation report
History
DepositionFeb 9, 2021-
Header (metadata) releaseApr 14, 2021-
Map releaseApr 14, 2021-
UpdateApr 14, 2021-
Current statusApr 14, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7lo6
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
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Supplemental images

Downloads & links

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Map

FileDownload / File: emd_23462.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 282.624 Å
1.1 Å/pix.
x 256 pix.
= 282.624 Å
1.1 Å/pix.
x 256 pix.
= 282.624 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.104 Å
Density
Contour LevelBy AUTHOR: 0.013 / Movie #1: 0.013
Minimum - Maximum-0.04089924 - 0.07888622
Average (Standard dev.)0.00025335126 (±0.0021521696)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 282.624 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1041.1041.104
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z282.624282.624282.624
α/β/γ90.00090.00090.000
start NX/NY/NZ645365
NX/NY/NZ139143124
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0410.0790.000

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Supplemental data

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Sample components

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Entire Complex of BG505 SOSIP.664 Env with CD4 mimetic BNM-III-170 and 1...

EntireName: Complex of BG505 SOSIP.664 Env with CD4 mimetic BNM-III-170 and 17b Fab
Number of components: 9

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Component #1: protein, Complex of BG505 SOSIP.664 Env with CD4 mimetic BNM-III-...

ProteinName: Complex of BG505 SOSIP.664 Env with CD4 mimetic BNM-III-170 and 17b Fab
Recombinant expression: No

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Component #2: protein, 17b Fab

ProteinName: 17b Fab
Details: Final reconstruction masked out the constant domain so only coordinates for the variable domain were modeled, but full Fab was used to assemble complex.
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Cell of expression system: HEK293

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Component #3: protein, BG505 SOSIP.664 HIV-1 Env trimer

ProteinName: BG505 SOSIP.664 HIV-1 Env trimer / Recombinant expression: No
SourceSpecies: Human immunodeficiency virus 1 / Strain: BG505
Source (engineered)Expression System: Homo sapiens (human) / Cell of expression system: HEK293

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Component #4: protein, Envelope glycoprotein BG505 SOSIP.664 gp120

ProteinName: Envelope glycoprotein BG505 SOSIP.664 gp120 / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 53.864086 kDa
SourceSpecies: Human immunodeficiency virus 1
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41

ProteinName: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41 / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 17.146482 kDa
SourceSpecies: Human immunodeficiency virus 1
Source (engineered)Expression System: Homo sapiens (human)

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Component #6: protein, 17b Fab Light Chain

ProteinName: 17b Fab Light Chain / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 23.399898 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #7: protein, 17b Fab Heavy Chain

ProteinName: 17b Fab Heavy Chain / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 25.748771 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #8: ligand, 2-acetamido-2-deoxy-beta-D-glucopyranose

LigandName: 2-acetamido-2-deoxy-beta-D-glucopyranose / Number of Copies: 27 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Component #9: ligand, ~{N}'-[(1~{R},2~{R})-2-(carbamimidamidomethyl)-5-(methyla...

LigandName: ~{N}'-[(1~{R},2~{R})-2-(carbamimidamidomethyl)-5-(methylaminomethyl)-2,3-dihydro-1~{H}-inden-1-yl]-~{N}-(4-chloranyl-3-fluoranyl-phenyl)ethanediamide
Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 0.446906 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 1.4 mg/mL / pH: 8
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 295.5 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 60 e/Å2 / Illumination mode: SPOT SCAN
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 662861
3D reconstructionSoftware: RELION / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Modeling #1Input PDB model: 6U0L, 5F4P, 2NXY
Output model

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