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- PDB-7shz: IgE-Fc in complex with HAE -

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Basic information

Entry
Database: PDB / ID: 7shz
TitleIgE-Fc in complex with HAE
Components
  • (HAE Variable fragment ...) x 2
  • IgE Fc
KeywordsIMMUNE SYSTEM / IgE / omalizumab / xolair / inhibitor / E27
Function / homology
Function and homology information


IgE B cell receptor complex / adaptive immune memory response / primary adaptive immune response / 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 ...IgE B cell receptor complex / adaptive immune memory response / primary adaptive immune response / 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 / antibody-dependent cellular cytotoxicity / Fc epsilon receptor (FCERI) signaling / mast cell degranulation / immunoglobulin complex, circulating / B cell proliferation / immunoglobulin receptor binding / macrophage differentiation / Role of LAT2/NTAL/LAB on calcium mobilization / complement activation, classical pathway / antigen binding / FCERI mediated Ca+2 mobilization / FCERI mediated MAPK activation / B cell receptor signaling pathway / FCERI mediated NF-kB activation / antibacterial humoral response / Interleukin-4 and Interleukin-13 signaling / adaptive immune response / immune response / inflammatory response / extracellular space / 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
ACETATE ION / alpha-D-mannopyranose / PHOSPHATE ION / 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 22, 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

Downloads & links

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Assembly

Deposited unit
B: IgE Fc
K: HAE Variable fragment Heavy chain
C: HAE Variable fragment Heavy chain
I: HAE Variable fragment Heavy chain
L: HAE Variable fragment Light chain
D: HAE Variable fragment Light chain
J: HAE Variable fragment Light chain
A: IgE Fc
H: IgE Fc
G: IgE Fc
E: HAE Variable fragment Heavy chain
F: HAE Variable fragment Light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,15326
Polymers222,60712
Non-polymers4,54614
Water48627
1
B: IgE Fc
C: HAE Variable fragment Heavy chain
D: HAE Variable fragment Light chain
A: IgE Fc
E: HAE Variable fragment Heavy chain
F: HAE Variable fragment Light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,33417
Polymers111,3036
Non-polymers3,03111
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
K: HAE Variable fragment Heavy chain
L: HAE Variable fragment Light chain
H: IgE Fc
hetero molecules

I: HAE Variable fragment Heavy chain
J: HAE Variable fragment Light chain
G: IgE Fc
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,8199
Polymers111,3036
Non-polymers1,5153
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_655-x+3/2,y+1/2,-z+1/21
Unit cell
Length a, b, c (Å)93.340, 187.340, 148.834
Angle α, β, γ (deg.)90.000, 103.131, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Components on special symmetry positions
IDModelComponents
11C-201-

PO4

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Components

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Protein , 1 types, 4 molecules BAHG

#1: 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 KCIELDJF

#2: Antibody
HAE Variable fragment Heavy chain


Mass: 13476.975 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody
HAE Variable fragment Light chain


Mass: 14623.840 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 , 5 types, 8 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-2)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-3)-[alpha-D- ...alpha-D-mannopyranose-(1-2)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-3)-[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: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2[DManpa1-6]DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-g1_d2-e1_d6-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: 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-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...alpha-D-mannopyranose-(1-3)-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
DManpa1-3DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-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]{}}}}}LINUCSPDB-CARE
#7: 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 / N-Acetylglucosamine


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
#11: Sugar ChemComp-MAN / alpha-D-mannopyranose / alpha-D-mannose / D-mannose / mannose / Mannose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 2
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 , 5 types, 33 molecules

#8: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#9: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#10: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#12: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 18.015 Da / Num. of mol.: 27 / 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: 2.85 Å3/Da / Density % sol: 56.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Sodium acetate pH 4.6, 8% (w/v) PEG 4000

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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: Dec 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 3→47.353 Å / Num. obs: 48998 / % possible obs: 98.2 % / Redundancy: 3.4 % / Biso Wilson estimate: 91.39 Å2 / CC1/2: 0.998 / Net I/σ(I): 12.94
Reflection shellResolution: 3→3.1 Å / Num. unique obs: 4592 / CC1/2: 0.844

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5hys

5hys


Resolution: 3→47.35 Å / SU ML: 0.4663 / Cross valid method: FREE R-VALUE / σ(F): 1.58 / Phase error: 29.364
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2355 1995 4.08 %
Rwork0.1861 46868 -
obs0.1882 48863 98.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 112.4 Å2
Refinement stepCycle: LAST / Resolution: 3→47.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13733 0 305 27 14065
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006614382
X-RAY DIFFRACTIONf_angle_d0.954219549
X-RAY DIFFRACTIONf_chiral_restr0.0672196
X-RAY DIFFRACTIONf_plane_restr0.00592478
X-RAY DIFFRACTIONf_dihedral_angle_d11.8935271
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.070.43281420.41833316X-RAY DIFFRACTION97.57
3.08-3.160.32261410.31773334X-RAY DIFFRACTION98.81
3.16-3.250.27721420.26113344X-RAY DIFFRACTION98.45
3.25-3.360.34591450.25993386X-RAY DIFFRACTION99.02
3.36-3.480.35171360.26583236X-RAY DIFFRACTION94.83
3.48-3.610.2411440.21443351X-RAY DIFFRACTION99.43
3.61-3.780.27711410.20393343X-RAY DIFFRACTION98.53
3.78-3.980.29081430.20193346X-RAY DIFFRACTION98.2
3.98-4.230.22481430.17843353X-RAY DIFFRACTION98.15
4.23-4.550.19461420.14663339X-RAY DIFFRACTION98.22
4.55-5.010.20771440.13783386X-RAY DIFFRACTION99.16
5.01-5.740.23561430.16153349X-RAY DIFFRACTION98.2
5.74-7.220.24451450.17913422X-RAY DIFFRACTION99.5
7.22-47.350.16571440.15953363X-RAY DIFFRACTION97.2

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