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- PDB-6x5b: Symmetric model of CD4- and 17-bound B41 HIV-1 Env SOSIP in compl... -

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Basic information

Entry
Database: PDB / ID: 6x5b
TitleSymmetric model of CD4- and 17-bound B41 HIV-1 Env SOSIP in complex with small molecule GO52
Components
  • (Envelope glycoprotein ...) x 2
  • 17b Fab heavy chain
  • 17b Fab light chain
  • T-cell surface glycoprotein CD4
KeywordsVIRAL PROTEIN / HIV-1 / Env / CD4 / receptor-bound state / small molecule / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / maintenance of protein location in cell / T cell selection / MHC class II protein binding / regulation of T cell activation / interleukin-15-mediated signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of kinase activity ...helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / maintenance of protein location in cell / T cell selection / MHC class II protein binding / regulation of T cell activation / interleukin-15-mediated signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of kinase activity / positive regulation of monocyte differentiation / Nef Mediated CD4 Down-regulation / Alpha-defensins / extracellular matrix structural constituent / T cell receptor complex / Other interleukin signaling / enzyme-linked receptor protein signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / regulation of calcium ion transport / macrophage differentiation / Generation of second messenger molecules / T cell differentiation / PD-1 signaling / positive regulation of protein kinase activity / Binding and entry of HIV virion / coreceptor activity / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / positive regulation of calcium-mediated signaling / protein tyrosine kinase binding / host cell endosome membrane / T cell activation / Vpu mediated degradation of CD4 / calcium-mediated signaling / clathrin-coated endocytic vesicle membrane / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of T cell activation / transmembrane signaling receptor activity / Cargo recognition for clathrin-mediated endocytosis / Downstream TCR signaling / MHC class II protein complex binding / Clathrin-mediated endocytosis / signaling receptor activity / virus receptor activity / clathrin-dependent endocytosis of virus by host cell / positive regulation of canonical NF-kappaB signal transduction / defense response to Gram-negative bacterium / adaptive immune response / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / positive regulation of viral entry into host cell / early endosome / cell surface receptor signaling pathway / viral protein processing / cell adhesion / immune response / positive regulation of protein phosphorylation / membrane raft / endoplasmic reticulum lumen / external side of plasma membrane / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / endoplasmic reticulum membrane / virion attachment to host cell / apoptotic process / protein kinase binding / host cell plasma membrane / positive regulation of DNA-templated transcription / structural molecule activity / virion membrane / enzyme binding / signal transduction / protein homodimerization activity / zinc ion binding / identical protein binding / plasma membrane
Similarity search - Function
CD4, extracellular / T cell CD4 receptor C-terminal region / CD4, extracellular / T cell CD4 receptor C terminal region / T-cell surface antigen CD4 / Immunoglobulin C2-set / Immunoglobulin C2-set domain / Immunoglobulin / Immunoglobulin domain / Envelope glycoprotein Gp160 ...CD4, extracellular / T cell CD4 receptor C-terminal region / CD4, extracellular / T cell CD4 receptor C terminal region / T-cell surface antigen CD4 / Immunoglobulin C2-set / Immunoglobulin C2-set domain / Immunoglobulin / Immunoglobulin domain / Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Chem-UOV / Envelope glycoprotein gp160 / Envelope glycoprotein gp160 / T-cell surface glycoprotein CD4
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsOzorowski, G. / Torres, J.L. / Ward, A.B.
Funding support United States, 3items
OrganizationGrant numberCountry
Other private109718-63-RKNT United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM069832 United States
Bill & Melinda Gates FoundationOPP1115782 United States
Citation
Journal: Cell Rep / Year: 2020
Title: A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.
Authors: Gabriel Ozorowski / Jonathan L Torres / Diogo Santos-Martins / Stefano Forli / Andrew B Ward /
Abstract: Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron ...Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.
#1: Journal: Biorxiv / Year: 2020
Title: A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide and offers a template for drug design
Authors: Ozorowski, G. / Torres, J.L. / Santos-Martins, D. / Forli, S. / Ward, A.B.
History
DepositionMay 25, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2020Group: Database references / Category: citation / citation_author

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Structure visualization

Movie
  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-22048
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Envelope glycoprotein gp120
B: Envelope glycoprotein gp41
L: 17b Fab light chain
C: T-cell surface glycoprotein CD4
H: 17b Fab heavy chain
D: Envelope glycoprotein gp120
E: Envelope glycoprotein gp41
F: 17b Fab light chain
G: T-cell surface glycoprotein CD4
I: 17b Fab heavy chain
J: Envelope glycoprotein gp120
K: Envelope glycoprotein gp41
M: 17b Fab light chain
N: T-cell surface glycoprotein CD4
O: 17b Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)452,52851
Polymers441,54115
Non-polymers10,98836
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Envelope glycoprotein ... , 2 types, 6 molecules ADJBEK

#1: Protein Envelope glycoprotein gp120 / Env polyprotein


Mass: 58872.902 Da / Num. of mol.: 3 / Mutation: A501C, E510R, K511R, 512R, 513R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: B41 / Gene: env / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: B3UES2
#2: Protein Envelope glycoprotein gp41


Mass: 17357.824 Da / Num. of mol.: 3 / Mutation: I559P, T605C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: B41 / Gene: env / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: B3UEZ6

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Antibody , 2 types, 6 molecules LFMHIO

#3: Antibody 17b Fab light chain


Mass: 23425.869 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#5: Antibody 17b Fab heavy chain


Mass: 24484.455 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)

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Protein / Non-polymers , 2 types, 6 molecules CGN

#4: Protein T-cell surface glycoprotein CD4 / T-cell surface antigen T4/Leu-3


Mass: 23039.172 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD4 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P01730
#9: Chemical ChemComp-UOV / N-(4'-methyl[1,1'-biphenyl]-4-yl)-1-oxa-7-azaspiro[3.5]nonane-7-carboxamide


Mass: 336.427 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H24N2O2 / Feature type: SUBJECT OF INVESTIGATION

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Sugars , 3 types, 33 molecules

#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_d2-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}}LINUCSPDB-CARE
#8: Sugar...
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 27
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: B41 HIV-1 Env SOSIP in complex with soluble CD4, 17b Fab, and small molecule GO52
Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.63 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Human immunodeficiency virus 111676
21Homo sapiens (human)9606
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
Details: Detergent diluted into sample shortly before application to grid
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
250 mMTris1
30.005 mMLauryl Maltose Neopentyl Glycol1
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 11.5 sec. / Electron dose: 49 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 2654
Image scansMovie frames/image: 46

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Processing

EM software
IDNameVersionCategory
1cryoSPARC2particle selection
2Leginonimage acquisition
4Gctf1.06CTF correction
7UCSF Chimeramodel fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
11RELION3classification
12RELION33D reconstruction
13Rosetta2020.03.61102model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 228502 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingPDB-ID: 5VN3

5vn3

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