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- PDB-8vbp: Structure of bovine anti-HIV Fab Bess4 -

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Basic information

Entry
Database: PDB / ID: 8vbp
TitleStructure of bovine anti-HIV Fab Bess4
Components
  • Bovine Fab Bess4 heavy chain
  • Bovine Fab Bess4 light chain
KeywordsIMMUNE SYSTEM / antibody / Fab fragment / bovine
Biological speciesBos taurus (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsStanfield, R.L. / Wilson, I.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationINV-034657 United States
CitationJournal: PLoS Pathog / Year: 2024
Title: Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire.
Authors: Pilar X Altman / Gabriel Ozorowski / Robyn L Stanfield / Jeremy Haakenson / Michael Appel / Mara Parren / Wen-Hsin Lee / Huldah Sang / Jordan Woehl / Karen Saye-Francisco / Leigh M Sewall / ...Authors: Pilar X Altman / Gabriel Ozorowski / Robyn L Stanfield / Jeremy Haakenson / Michael Appel / Mara Parren / Wen-Hsin Lee / Huldah Sang / Jordan Woehl / Karen Saye-Francisco / Leigh M Sewall / Collin Joyce / Ge Song / Katelyn Porter / Elise Landais / Raiees Andrabi / Ian A Wilson / Andrew B Ward / Waithaka Mwangi / Vaughn V Smider / Dennis R Burton / Devin Sok /
Abstract: The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do ...The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response.
History
DepositionDec 12, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: Bovine Fab Bess4 light chain
H: Bovine Fab Bess4 heavy chain


Theoretical massNumber of molelcules
Total (without water)50,7202
Polymers50,7202
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3770 Å2
ΔGint-23 kcal/mol
Surface area20380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.607, 70.283, 111.459
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Antibody Bovine Fab Bess4 light chain


Mass: 22527.611 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Cell line (production host): expi293F / Organ (production host): kidney / Production host: Homo sapiens (human)
#2: Antibody Bovine Fab Bess4 heavy chain


Mass: 28192.430 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Organ (production host): kidney / Production host: Homo sapiens (human)

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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: 2.57 Å3/Da / Density % sol: 52.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 70% MPD, 0.1M Hepes, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.97946 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 19, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.8→29.94 Å / Num. obs: 12710 / % possible obs: 93.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.5 % / Biso Wilson estimate: 38.12 Å2 / CC1/2: 0.973 / Rmerge(I) obs: 0.191 / Rpim(I) all: 0.115 / Rrim(I) all: 0.224 / Net I/σ(I): 7
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.805 / Mean I/σ(I) obs: 3 / Num. unique obs: 1143 / CC1/2: 0.498 / Rpim(I) all: 0.51 / Rrim(I) all: 0.959 / % possible all: 87.2

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→29.94 Å / SU ML: 0.3491 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.3652
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2317 620 4.93 %
Rwork0.1965 11960 -
obs0.1984 12580 93.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.27 Å2
Refinement stepCycle: LAST / Resolution: 2.8→29.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3248 0 0 0 3248
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00283327
X-RAY DIFFRACTIONf_angle_d0.57644548
X-RAY DIFFRACTIONf_chiral_restr0.0431543
X-RAY DIFFRACTIONf_plane_restr0.0045578
X-RAY DIFFRACTIONf_dihedral_angle_d10.82061180
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-3.080.31891510.25212888X-RAY DIFFRACTION92.4
3.08-3.520.26281700.22292989X-RAY DIFFRACTION95.41
3.52-4.440.20371410.17972978X-RAY DIFFRACTION93.44
4.44-29.940.20181580.1743105X-RAY DIFFRACTION93.6

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