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- PDB-7u5g: ACS122 Fab -

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Basic information

Entry
Database: PDB / ID: 7u5g
TitleACS122 Fab
Components
  • ACS122 Fab Heavy chain
  • ACS122 Fab Light chain
KeywordsIMMUNE SYSTEM / gp41-gp120 interface
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsFarokhi, E. / Stanfield, R.L. / Wilson, I.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Consortia for HIV/AIDS Vaccine Development United States
CitationJournal: PLoS Pathog / Year: 2022
Title: Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer.
Authors: Jelle van Schooten / Anna Schorcht / Elinaz Farokhi / Jeffrey C Umotoy / Hongmei Gao / Tom L G M van den Kerkhof / Jessica Dorning / Tim G Rijkhold Meesters / Patricia van der Woude / Judith ...Authors: Jelle van Schooten / Anna Schorcht / Elinaz Farokhi / Jeffrey C Umotoy / Hongmei Gao / Tom L G M van den Kerkhof / Jessica Dorning / Tim G Rijkhold Meesters / Patricia van der Woude / Judith A Burger / Tom Bijl / Riham Ghalaiyini / Alba Torrents de la Peña / Hannah L Turner / Celia C Labranche / Robyn L Stanfield / Devin Sok / Hanneke Schuitemaker / David C Montefiori / Dennis R Burton / Gabriel Ozorowski / Michael S Seaman / Ian A Wilson / Rogier W Sanders / Andrew B Ward / Marit J van Gils /
Abstract: Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely ...Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely difficult to induce by vaccination. Defining the developmental pathways towards neutralization breadth can assist in the design of strategies to elicit protective bNAb responses by vaccination. Here, HIV-1 envelope glycoproteins (Env)-specific IgG+ B cells were isolated at various time points post infection from an HIV-1 infected elite neutralizer to obtain monoclonal antibodies (mAbs). Multiple antibody lineages were isolated targeting distinct epitopes on Env, including the gp120-gp41 interface, CD4-binding site, silent face and V3 region. The mAbs each neutralized a diverse set of HIV-1 strains from different clades indicating that the patient's remarkable serum breadth and potency might have been the result of a polyclonal mixture rather than a single bNAb lineage. High-resolution cryo-electron microscopy structures of the neutralizing mAbs (NAbs) in complex with an Env trimer generated from the same individual revealed that the NAbs used multiple strategies to neutralize the virus; blocking the receptor binding site, binding to HIV-1 Env N-linked glycans, and disassembly of the trimer. These results show that diverse NAbs can complement each other to achieve a broad and potent neutralizing serum response in HIV-1 infected individuals. Hence, the induction of combinations of moderately broad NAbs might be a viable vaccine strategy to protect against a wide range of circulating HIV-1 viruses.
History
DepositionMar 2, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: 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
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: ACS122 Fab Heavy chain
L: ACS122 Fab Light chain


Theoretical massNumber of molelcules
Total (without water)47,4982
Polymers47,4982
Non-polymers00
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4010 Å2
ΔGint-27 kcal/mol
Surface area19810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.402, 70.445, 97.324
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 ACS122 Fab Heavy chain


Mass: 24485.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#2: Antibody ACS122 Fab Light chain


Mass: 23012.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 70 / Source method: isolated from a natural source / Formula: H2O

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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: 2.32 Å3/Da / Density % sol: 47.07 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 0.1M of Tris (pH 8.5) and 55%(v/v) 2-methyl-2,4-pentanediol

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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: May 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.84→35.22 Å / Num. obs: 39554 / % possible obs: 99.4 % / Redundancy: 11.5 % / Biso Wilson estimate: 32 Å2 / CC1/2: 0.76 / Rmerge(I) obs: 0.186 / Rpim(I) all: 0.056 / Rrim(I) all: 0.195 / Net I/σ(I): 12.1
Reflection shellResolution: 1.85→1.88 Å / Rmerge(I) obs: 1.01 / Num. unique obs: 1817 / CC1/2: 0.35 / Rpim(I) all: 0.57 / Rrim(I) all: 1.16

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F7E

5f7e


Resolution: 1.84→35.22 Å / SU ML: 0.2705 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.6912
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2564 1839 4.89 %
Rwork0.2217 35791 -
obs0.2234 37630 95.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.3 Å2
Refinement stepCycle: LAST / Resolution: 1.84→35.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3320 0 0 70 3390
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01673410
X-RAY DIFFRACTIONf_angle_d1.28624662
X-RAY DIFFRACTIONf_chiral_restr0.0764531
X-RAY DIFFRACTIONf_plane_restr0.0106596
X-RAY DIFFRACTIONf_dihedral_angle_d14.67191219
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.84-1.890.3531180.32062449X-RAY DIFFRACTION86.61
1.89-1.940.35521480.30822776X-RAY DIFFRACTION97.99
1.94-20.32921590.29792757X-RAY DIFFRACTION97.92
2-2.080.3271310.28382775X-RAY DIFFRACTION96.74
2.08-2.160.28571340.26912488X-RAY DIFFRACTION88.08
2.16-2.260.33251390.26992783X-RAY DIFFRACTION97.82
2.26-2.380.30891420.26052833X-RAY DIFFRACTION98.9
2.38-2.530.26521510.25242809X-RAY DIFFRACTION98.57
2.53-2.720.24951340.25442843X-RAY DIFFRACTION98.32
2.72-2.990.30191400.24242774X-RAY DIFFRACTION96.3
2.99-3.430.25341450.22882716X-RAY DIFFRACTION93.68
3.43-4.320.241430.18492893X-RAY DIFFRACTION98.32
4.32-35.220.19891550.17492895X-RAY DIFFRACTION94.66

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