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- PDB-5u1f: Initial contact of HIV-1 Env with CD4: Cryo-EM structure of BG505... -

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Basic information

Entry
Database: PDB / ID: 5u1f
TitleInitial contact of HIV-1 Env with CD4: Cryo-EM structure of BG505 DS-SOSIP trimer in complex with CD4 and antibody PGT145
Components
  • BG505 DS-SOSIP gp120
  • BG505 SOSIP gp41
  • PGT145 heavy chain
  • PGT145 light chain
  • T-cell surface glycoprotein CD4
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV-1 Entry early intermediate / CD4 binding site / 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 / response to methamphetamine hydrochloride / maintenance of protein location in cell / cellular response to ionomycin / T cell selection / MHC class II protein binding / positive regulation of kinase activity / interleukin-15-mediated signaling pathway ...helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / response to methamphetamine hydrochloride / maintenance of protein location in cell / cellular response to ionomycin / T cell selection / MHC class II protein binding / positive regulation of kinase activity / interleukin-15-mediated signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of monocyte differentiation / Nef Mediated CD4 Down-regulation / Alpha-defensins / regulation of T cell activation / response to vitamin D / extracellular matrix structural constituent / Other interleukin signaling / T cell receptor complex / enzyme-linked receptor protein signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / positive regulation of protein kinase activity / regulation of calcium ion transport / positive regulation of calcium ion transport into cytosol / macrophage differentiation / Generation of second messenger molecules / immunoglobulin binding / T cell differentiation / Co-inhibition by PD-1 / Binding and entry of HIV virion / coreceptor activity / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of T cell proliferation / positive regulation of interleukin-2 production / positive regulation of calcium-mediated signaling / cell surface receptor protein tyrosine kinase signaling pathway / protein tyrosine kinase binding / host cell endosome membrane / Vpu mediated degradation of CD4 / clathrin-coated endocytic vesicle membrane / calcium-mediated signaling / positive regulation of protein phosphorylation / MHC class II protein complex binding / transmembrane signaling receptor activity / Downstream TCR signaling / response to estradiol / Cargo recognition for clathrin-mediated endocytosis / signaling receptor activity / Clathrin-mediated endocytosis / virus receptor activity / response to ethanol / defense response to Gram-negative bacterium / clathrin-dependent endocytosis of virus by host cell / adaptive immune response / positive regulation of viral entry into host cell / early endosome / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / positive regulation of canonical NF-kappaB signal transduction / cell adhesion / positive regulation of MAPK cascade / viral protein processing / immune response / membrane raft / endoplasmic reticulum lumen / fusion of virus membrane with host plasma membrane / external side of plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / lipid binding / symbiont entry into host cell / endoplasmic reticulum membrane / protein kinase binding / positive regulation of DNA-templated transcription / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / enzyme binding / signal transduction / protein homodimerization activity / zinc ion binding / identical protein binding / membrane / 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
T-cell surface glycoprotein CD4 / Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsAcharya, P. / Kwong, P.D. / Potter, C.S. / Carragher, B.
CitationJournal: Nat Struct Mol Biol / Year: 2017
Title: Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer.
Authors: Qingbo Liu / Priyamvada Acharya / Michael A Dolan / Peng Zhang / Christina Guzzo / Jacky Lu / Alice Kwon / Deepali Gururani / Huiyi Miao / Tatsiana Bylund / Gwo-Yu Chuang / Aliaksandr Druz / ...Authors: Qingbo Liu / Priyamvada Acharya / Michael A Dolan / Peng Zhang / Christina Guzzo / Jacky Lu / Alice Kwon / Deepali Gururani / Huiyi Miao / Tatsiana Bylund / Gwo-Yu Chuang / Aliaksandr Druz / Tongqing Zhou / William J Rice / Christoph Wigge / Bridget Carragher / Clinton S Potter / Peter D Kwong / Paolo Lusso /
Abstract: Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial ...Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1-Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurred after the mutation of CD4 residues that interact with CD4-BS2. Our results document the critical role of quaternary interactions in the initial HIV-Env-receptor contact, with implications for treatment and vaccine design.
History
DepositionNov 28, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2017Group: Database references
Revision 1.2Apr 19, 2017Group: Database references
Revision 1.3Mar 7, 2018Group: Data collection / Structure summary / Category: em_software / struct / Item: _em_software.name / _struct.title
Revision 1.4Jul 18, 2018Group: Data collection / Category: em_software / Item: _em_software.name
Revision 1.5Oct 3, 2018Group: Data collection / Refinement description / Category: refine / Item: _refine.pdbx_refine_id
Revision 1.6Nov 13, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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  • EMDB-8427
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Structure viewerMolecule:
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Assembly

Deposited unit
C: BG505 DS-SOSIP gp120
D: BG505 DS-SOSIP gp120
A: BG505 DS-SOSIP gp120
B: BG505 SOSIP gp41
E: BG505 SOSIP gp41
F: BG505 SOSIP gp41
H: PGT145 heavy chain
L: PGT145 light chain
M: T-cell surface glycoprotein CD4


Theoretical massNumber of molelcules
Total (without water)323,6929
Polymers323,6929
Non-polymers00
Water00
1


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

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Components

#1: Protein BG505 DS-SOSIP gp120


Mass: 55875.484 Da / Num. of mol.: 3 / Fragment: UNP residues 29-502
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Plasmid: pVRC8400 / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6
#2: Protein BG505 SOSIP gp41


Mass: 20202.158 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6
#3: Antibody PGT145 heavy chain


Mass: 28953.285 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody PGT145 light chain


Mass: 26050.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Protein T-cell surface glycoprotein CD4 / T-cell surface antigen T4/Leu-3


Mass: 40455.477 Da / Num. of mol.: 1 / Fragment: UNP residues 26-388
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD4 / Production host: Homo sapiens (human) / References: UniProt: P01730
Has protein modificationY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of BG505 DS-SOSIP, PGT145 and CD4COMPLEXall0RECOMBINANT
2HIV-1 trimerCOMPLEX#1-#21RECOMBINANT
3Antibody PGT145COMPLEX#3-#41RECOMBINANT
4CD4COMPLEX#51RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.31 MDaYES
210.225 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Human immunodeficiency virus 111676
22Human immunodeficiency virus 111676
33Homo sapiens (human)9606
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDPlasmid
11Homo sapiens (human)9606pVRC8400
22Homo sapiens (human)9606pVRC8400
33Homo sapiens (human)9606pVRC8400
44Homo sapiens (human)9606pVRC8400
Buffer solutionpH: 7.5
Buffer componentConc.: 5 mM / Name: HEPES
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Monodisperse specimen
Specimen supportGrid material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 8.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 1900
Image scansMovie frames/image: 40 / Used frames/image: 1-30

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Processing

EM software
IDNameVersionCategory
1DoG Pickerparticle selection
2Leginon3.1image acquisition
4GctfCTF correction
7UCSF Chimera1.11.2model fitting
10RELION1.4final Euler assignment
11RELION1.4classification
12RELION1.43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 55000 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Target criteria: Correlation Coefficient
RefinementHighest resolution: 6.8 Å

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