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- PDB-7shy: IgE-Fc in complex with omalizumab scFv -

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Basic information

Entry
Database: PDB / ID: 7shy
TitleIgE-Fc in complex with omalizumab scFv
Components
  • IgE Fc
  • Omalizumab VH
  • Omalizumab VL
KeywordsIMMUNE SYSTEM / IgE / omalizumab / xolair / inhibitor
Function / homology
Function and homology information


adaptive immune memory response / primary adaptive immune response / IgE B cell receptor complex / type I hypersensitivity / B cell antigen processing and presentation / Fc receptor-mediated immune complex endocytosis / eosinophil degranulation / IgE immunoglobulin complex / macrophage activation / type 2 immune response ...adaptive immune memory response / primary adaptive immune response / IgE B cell receptor complex / type I hypersensitivity / B cell antigen processing and presentation / Fc receptor-mediated immune complex endocytosis / eosinophil degranulation / IgE immunoglobulin complex / macrophage activation / type 2 immune response / Fc epsilon receptor (FCERI) signaling / antibody-dependent cellular cytotoxicity / mast cell degranulation / B cell proliferation / macrophage differentiation / Role of LAT2/NTAL/LAB on calcium mobilization / immunoglobulin complex, circulating / immunoglobulin receptor binding / FCERI mediated Ca+2 mobilization / complement activation, classical pathway / FCERI mediated MAPK activation / antigen binding / B cell receptor signaling pathway / FCERI mediated NF-kB activation / antibacterial humoral response / Interleukin-4 and Interleukin-13 signaling / adaptive immune response / blood microparticle / inflammatory response / immune response / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
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 / Immunoglobulin-like fold
Similarity search - Domain/homology
alpha-D-mannopyranose / Immunoglobulin heavy constant epsilon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsPennington, L.F. / Jardetzky, T.J. / Kleinboelting, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI115469 United States
CitationJournal: Nat Commun / Year: 2021
Title: Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex.
Authors: Luke F Pennington / Pascal Gasser / Silke Kleinboelting / Chensong Zhang / Georgios Skiniotis / Alexander Eggel / Theodore S Jardetzky /
Abstract: Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional ...Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated "disruption" of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells.
History
DepositionOct 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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

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Assembly

Deposited unit
I: Omalizumab VH
K: Omalizumab VH
C: Omalizumab VH
J: Omalizumab VL
L: Omalizumab VL
D: Omalizumab VL
A: IgE Fc
G: IgE Fc
H: IgE Fc
E: Omalizumab VH
F: Omalizumab VL
B: IgE Fc
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,36721
Polymers222,31812
Non-polymers5,0509
Water1086
1
I: Omalizumab VH
K: Omalizumab VH
J: Omalizumab VL
L: Omalizumab VL
G: IgE Fc
H: IgE Fc
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,38210
Polymers111,1596
Non-polymers2,2234
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Omalizumab VH
D: Omalizumab VL
A: IgE Fc
E: Omalizumab VH
F: Omalizumab VL
B: IgE Fc
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,98511
Polymers111,1596
Non-polymers2,8275
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)157.500, 179.090, 91.520
Angle α, β, γ (deg.)90.000, 111.660, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 4 molecules AGHB

#3: Protein
IgE Fc / Immunoglobulin heavy constant epsilon / Ig epsilon chain C region / Ig epsilon chain C region ND


Mass: 27550.873 Da / Num. of mol.: 4 / Fragment: C3-4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGHE / Production host: Homo sapiens (human) / References: UniProt: P01854

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Antibody , 2 types, 8 molecules IKCEJLDF

#1: Antibody
Omalizumab VH


Mass: 13362.744 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody
Omalizumab VL


Mass: 14665.836 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 6 types, 8 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(2-3)-[alpha-L-fucopyranose-(1-6)]beta-D- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(2-3)-[alpha-L-fucopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1056.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa2-3[LFucpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(4+1)][a-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+2)][D-1-deoxy-Glcp]{[(3+1)][a-D-Manp]{}}[(6+1)][a-L-Fucp]{}}}}}LINUCSPDB-CARE
#5: Polysaccharide beta-D-mannopyranose-(1-4)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...beta-D-mannopyranose-(1-4)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(4+1)][b-D-Manp]{}}}}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(3+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}}LINUCSPDB-CARE
#9: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#10: Sugar ChemComp-MAN / alpha-D-mannopyranose / alpha-D-mannose / D-mannose / mannose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C6H12O6
IdentifierTypeProgram
DManpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-mannopyranoseCOMMON NAMEGMML 1.0
a-D-ManpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
ManSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 7 molecules

#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.7 Å3/Da / Density % sol: 54.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.02 M Magnesium chloride, 0.1M HEPES pH 7.5, 22% (w/v) Polyacrylic acid 5100 sodium salt

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 3→39.93 Å / Num. obs: 160286 / % possible obs: 98 % / Redundancy: 3.5 % / CC1/2: 0.998 / Net I/σ(I): 11.78
Reflection shellResolution: 3→3.107 Å / Mean I/σ(I) obs: 1.29 / Num. unique obs: 16540 / CC1/2: 0.635

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.14refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5hys

5hys


Resolution: 3→39.93 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflection
Rfree0.2299 --
Rwork0.1731 --
obs-160286 98 %
Displacement parametersBiso max: 266.83 Å2 / Biso mean: 99.1952 Å2 / Biso min: 39 Å2
Refinement stepCycle: LAST / Resolution: 3→39.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13786 0 335 6 14127

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