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- PDB-8d54: anti HIV gp120/CD4 complex antibody CG10 Fab -

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Basic information

Entry
Database: PDB / ID: 8d54
Titleanti HIV gp120/CD4 complex antibody CG10 Fab
Components
  • CG10 Fab heavy chain
  • CG10 Fab light chain
KeywordsIMMUNE SYSTEM / HIV-1 antibody
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsYang, Z. / Bjorkman, P.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HIVRAD P01 AI100148 United States
Bill & Melinda Gates FoundationCAVD INV-002143 United States
CitationJournal: J Virol / Year: 2022
Title: Antibody Recognition of CD4-Induced Open HIV-1 Env Trimers.
Authors: Zhi Yang / Kim-Marie A Dam / Jonathan M Gershoni / Susan Zolla-Pazner / Pamela J Bjorkman /
Abstract: Human immunodeficiency virus type 1 (HIV-1) envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 ...Human immunodeficiency virus type 1 (HIV-1) envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. In this study, we characterized a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i MAbs) that displayed characteristics of CD4i antibodies. Binding experiments demonstrated that the V2i MAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i MAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy showed recognition by V2i MAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the MAbs with CD4. We also characterized CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, bound to an Env trimer plus CD4. CG10 exhibited characteristics similar to those of the V2i antibodies, i.e., recognition of the open Env conformation, but showed direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection. The RV144 HIV-1 clinical vaccination trial showed modest protection against viral infection. Antibody responses to the V1V2 region of HIV-1 Env gp120 were correlated inversely with the risk of infection, and data from three other clinical vaccine trials suggested a similar signal. In addition, antibodies targeting V1V2 have been correlated with protections from simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infections in nonhuman primates. We structurally characterized V2i antibodies directed against V1V2 isolated from HIV-1 infected humans in complex with open Env trimers bound to the host receptor CD4. We also characterized a CD4i antibody that interacts with CD4 as well as the gp120 subunit of an open Env trimer. Our study suggests how V2i and CD4i antibodies were elicited during HIV-1 infection.
History
DepositionJun 3, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 14, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CG10 Fab heavy chain
B: CG10 Fab light chain


Theoretical massNumber of molelcules
Total (without water)48,3172
Polymers48,3172
Non-polymers00
Water10,251569
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3760 Å2
ΔGint-30 kcal/mol
Surface area19920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.137, 77.801, 84.025
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody CG10 Fab heavy chain


Mass: 24583.389 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
#2: Antibody CG10 Fab light chain


Mass: 23733.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 569 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.54 Å3/Da / Density % sol: 51.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 14% (w/v) PEG 4,000, 0.1M MES (pH 6.6)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.4→38.9 Å / Num. obs: 97069 / % possible obs: 99.5 % / Redundancy: 13.3 % / CC1/2: 0.99 / Net I/σ(I): 19.6
Reflection shellResolution: 1.4→1.42 Å / Rmerge(I) obs: 1.51 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 4660 / CC1/2: 0.63 / Rpim(I) all: 0.43

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Processing

Software
NameVersionClassification
PHENIXv1.19.2refinement
Aimlessdata scaling
PDB_EXTRACT3.27data extraction
TRUNCATEdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CMH

4cmh


Resolution: 1.4→38.9 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflection
Rfree0.188 --
Rwork0.169 --
obs-97069 99.5 %
Displacement parametersBiso max: 129.89 Å2 / Biso mean: 25.069 Å2 / Biso min: 11.32 Å2
Refinement stepCycle: LAST / Resolution: 1.4→38.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3355 0 0 569 3924

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