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- PDB-6okq: Crystal structure of the SF12 Fab -

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Basic information

Entry
Database: PDB / ID: 6okq
TitleCrystal structure of the SF12 Fab
Components
  • SF12 Fab Heavy Chain,SF12 Fab Heavy Chain
  • SF12 Fab Light Chain,SF12 Fab Light Chain
KeywordsIMMUNE SYSTEM / HIV-1 broadly-neutralizing antibody / Fab structure / silent face / Envelope
Function / homology
Function and homology information


immunoglobulin complex / adaptive immune response / extracellular region / membrane / plasma membrane
Similarity search - Function
Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain ...Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Immunoglobulin gamma-1 heavy chain / Ig-like domain-containing protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsBarnes, C.O. / Bjorkman, P.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01 AI100148 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P50 GM082545-06 United States
CitationJournal: Immunity / Year: 2019
Title: Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope.
Authors: Till Schoofs / Christopher O Barnes / Nina Suh-Toma / Jovana Golijanin / Philipp Schommers / Henning Gruell / Anthony P West / Franziska Bach / Yu Erica Lee / Lilian Nogueira / Ivelin S ...Authors: Till Schoofs / Christopher O Barnes / Nina Suh-Toma / Jovana Golijanin / Philipp Schommers / Henning Gruell / Anthony P West / Franziska Bach / Yu Erica Lee / Lilian Nogueira / Ivelin S Georgiev / Robert T Bailer / Julie Czartoski / John R Mascola / Michael S Seaman / M Juliana McElrath / Nicole A Doria-Rose / Florian Klein / Michel C Nussenzweig / Pamela J Bjorkman /
Abstract: Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization ...Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.
History
DepositionApr 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 5, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2019Group: Data collection / Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: SF12 Fab Heavy Chain,SF12 Fab Heavy Chain
B: SF12 Fab Light Chain,SF12 Fab Light Chain
C: SF12 Fab Light Chain,SF12 Fab Light Chain
D: SF12 Fab Heavy Chain,SF12 Fab Heavy Chain
E: SF12 Fab Light Chain,SF12 Fab Light Chain
F: SF12 Fab Heavy Chain,SF12 Fab Heavy Chain


Theoretical massNumber of molelcules
Total (without water)147,7936
Polymers147,7936
Non-polymers00
Water0
1
A: SF12 Fab Heavy Chain,SF12 Fab Heavy Chain
B: SF12 Fab Light Chain,SF12 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)49,2642
Polymers49,2642
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3470 Å2
ΔGint-17 kcal/mol
Surface area19740 Å2
MethodPISA
2
C: SF12 Fab Light Chain,SF12 Fab Light Chain
D: SF12 Fab Heavy Chain,SF12 Fab Heavy Chain


Theoretical massNumber of molelcules
Total (without water)49,2642
Polymers49,2642
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3560 Å2
ΔGint-20 kcal/mol
Surface area19580 Å2
MethodPISA
3
E: SF12 Fab Light Chain,SF12 Fab Light Chain
F: SF12 Fab Heavy Chain,SF12 Fab Heavy Chain


Theoretical massNumber of molelcules
Total (without water)49,2642
Polymers49,2642
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3520 Å2
ΔGint-19 kcal/mol
Surface area19600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)223.018, 223.018, 288.296
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222

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Components

#1: Antibody SF12 Fab Heavy Chain,SF12 Fab Heavy Chain


Mass: 26155.338 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTT5 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P0DOX5
#2: Antibody SF12 Fab Light Chain,SF12 Fab Light Chain


Mass: 23108.842 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTT5 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8TCD0

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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: 7 Å3/Da / Density % sol: 82.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 100 mM HEPES, pH 7.5, 1.8 M sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 19, 2018
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→39.28 Å / Num. obs: 70865 / % possible obs: 99.6 % / Redundancy: 60.4 % / Biso Wilson estimate: 81.6 Å2 / Rmerge(I) obs: 0.216 / Net I/σ(I): 22.8
Reflection shellResolution: 3.2→3.26 Å / Redundancy: 56.8 % / Rmerge(I) obs: 2.55 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 4473 / % possible all: 98.7

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Processing

Software
NameVersionClassification
PHENIX(1.14_3219: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1U6A
Resolution: 3.2→39.25 Å / SU ML: 0.46 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 40.91
RfactorNum. reflection% reflection
Rfree0.299 3451 4.95 %
Rwork0.273 --
obs0.275 69737 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.2→39.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10056 0 0 0 10056
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0110311
X-RAY DIFFRACTIONf_angle_d1.41414049
X-RAY DIFFRACTIONf_dihedral_angle_d13.7786162
X-RAY DIFFRACTIONf_chiral_restr0.0741581
X-RAY DIFFRACTIONf_plane_restr0.011794
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2-3.24380.58311390.55872549X-RAY DIFFRACTION98
3.2438-3.29020.50861180.532587X-RAY DIFFRACTION99
3.2902-3.33920.53231350.49082629X-RAY DIFFRACTION99
3.3392-3.39140.52171380.49112597X-RAY DIFFRACTION100
3.3914-3.4470.50441420.47852598X-RAY DIFFRACTION100
3.447-3.50640.48791270.44442616X-RAY DIFFRACTION99
3.5064-3.57010.48391390.43242607X-RAY DIFFRACTION99
3.5701-3.63870.41811340.382613X-RAY DIFFRACTION100
3.6387-3.71290.40381660.37392613X-RAY DIFFRACTION100
3.7129-3.79360.35871280.34722621X-RAY DIFFRACTION99
3.7936-3.88180.33981290.31592625X-RAY DIFFRACTION100
3.8818-3.97870.29381440.30682639X-RAY DIFFRACTION100
3.9787-4.08620.27831230.27632643X-RAY DIFFRACTION100
4.0862-4.20630.25851520.27172638X-RAY DIFFRACTION100
4.2063-4.34190.2521440.25192627X-RAY DIFFRACTION100
4.3419-4.49690.29691140.21982670X-RAY DIFFRACTION100
4.4969-4.67670.23241360.22232630X-RAY DIFFRACTION99
4.6767-4.88910.27541400.21872657X-RAY DIFFRACTION100
4.8891-5.14640.27631530.22762660X-RAY DIFFRACTION100
5.1464-5.4680.27881510.23372667X-RAY DIFFRACTION100
5.468-5.88890.26411330.23942703X-RAY DIFFRACTION100
5.8889-6.47910.26961360.25052694X-RAY DIFFRACTION100
6.4791-7.41120.28331230.2532737X-RAY DIFFRACTION100
7.4112-9.31670.20991460.21592772X-RAY DIFFRACTION100
9.3167-39.24760.25911610.22692894X-RAY DIFFRACTION99

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