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- PDB-4zd3: Structure of a transglutaminase 2-specific autoantibody Fab fragment -

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Basic information

Entry
Database: PDB / ID: 4zd3
TitleStructure of a transglutaminase 2-specific autoantibody Fab fragment
Components
  • 679-14-14E06 Fab fragment heavy chain
  • 679-14-14E06 Fab fragment light chain
KeywordsIMMUNE SYSTEM / transglutaminase 2 / antibody / Fab fragment / celiac disease
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsChen, X. / Dalhus, B. / Hnida, K. / Iversen, R. / Sollid, L.M.
Funding support Norway, 4items
OrganizationGrant numberCountry
South-Eastern Norway Regional Health Authority Norway
Research Council of Norway179573/V40 Norway
European Communitys Seventh Framework ProgrammeMRTN-CT-2011-289964 Norway
European Communitys Seventh Framework ProgrammeERC-2010-Ad-268541 Norway
CitationJournal: J Biol Chem / Year: 2015
Title: Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease.
Authors: Xi Chen / Kathrin Hnida / Melissa Ann Graewert / Jan Terje Andersen / Rasmus Iversen / Anne Tuukkanen / Dmitri Svergun / Ludvig M Sollid /
Abstract: Antibodies to the autoantigen transglutaminase 2 (TG2) are a hallmark of celiac disease. We have studied the interaction between TG2 and an anti-TG2 antibody (679-14-E06) derived from a single gut ...Antibodies to the autoantigen transglutaminase 2 (TG2) are a hallmark of celiac disease. We have studied the interaction between TG2 and an anti-TG2 antibody (679-14-E06) derived from a single gut IgA plasma cell of a celiac disease patient. The antibody recognizes one of four identified epitopes targeted by antibodies of plasma cells of the disease lesion. The binding interface was identified by small angle x-ray scattering, ab initio and rigid body modeling using the known crystal structure of TG2 and the crystal structure of the antibody Fab fragment, which was solved at 2.4 Å resolution. The result was confirmed by testing binding of the antibody to TG2 mutants by ELISA and surface plasmon resonance. TG2 residues Arg-116 and His-134 were identified to be critical for binding of 679-14-E06 as well as other epitope 1 antibodies. In contrast, antibodies directed toward the two other main epitopes (epitopes 2 and 3) were not affected by these mutations. Molecular dynamics simulations suggest interactions of 679-14-E06 with the N-terminal domain of TG2 via the CDR2 and CDR3 loops of the heavy chain and the CDR2 loop of the light chain. In addition there were contacts of the framework 3 region of the heavy chain with the catalytic domain of TG2. The results provide an explanation for the biased usage of certain heavy and light chain gene segments by epitope 1-specific antibodies in celiac disease.
History
DepositionApr 16, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 22, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_audit_support / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 679-14-14E06 Fab fragment heavy chain
L: 679-14-14E06 Fab fragment light chain


Theoretical massNumber of molelcules
Total (without water)47,7012
Polymers47,7012
Non-polymers00
Water1,40578
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3340 Å2
ΔGint-22 kcal/mol
Surface area18250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.340, 61.380, 79.050
Angle α, β, γ (deg.)90.00, 100.90, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Antibody 679-14-14E06 Fab fragment heavy chain


Mass: 24026.963 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody 679-14-14E06 Fab fragment light chain


Mass: 23674.209 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 78 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.17 % / Description: crystals look like plates
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.01 M nickel (II) chloride hexahydrate, 0.1 M Tris pH=8.5, 20% w/v polyethylene glycol monomethyl ether 2000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM30A / Wavelength: 0.979093 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 22, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979093 Å / Relative weight: 1
ReflectionResolution: 2.4→49.53 Å / Num. obs: 18701 / % possible obs: 99.2 % / Redundancy: 3.4 % / Rsym value: 0.117 / Net I/σ(I): 9.3
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.605 / Mean I/σ(I) obs: 2.4 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
MOSFLM7.1.0data reduction
Aimless5.8.0049data scaling
PHASER5.8.0049phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Contant and variable domains of heavy chain PDB code 4HPO and a light chain PDB code 1DFB

4hpo

1dfb


Resolution: 2.4→49.432 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2638 943 5.1 %RANDOM
Rwork0.2004 ---
obs0.2037 18508 98.98 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→49.432 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3097 0 0 78 3175
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093179
X-RAY DIFFRACTIONf_angle_d1.2774317
X-RAY DIFFRACTIONf_dihedral_angle_d15.0331128
X-RAY DIFFRACTIONf_chiral_restr0.052480
X-RAY DIFFRACTIONf_plane_restr0.006543
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.52660.2761350.22342488X-RAY DIFFRACTION99
2.5266-2.68480.32811310.23192494X-RAY DIFFRACTION99
2.6848-2.89210.32441350.22832481X-RAY DIFFRACTION99
2.8921-3.18310.30391400.22122515X-RAY DIFFRACTION99
3.1831-3.64360.25251080.19412523X-RAY DIFFRACTION99
3.6436-4.590.22531480.17062513X-RAY DIFFRACTION99
4.59-49.44230.24171460.19212551X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.4625-0.322-0.33442.60461.19352.32470.06920.12310.0306-0.1106-0.12410.09330.0099-0.11630.02510.1265-0.0041-0.04140.10840.02130.194517.6485-11.8788-2.2403
22.33721.325-0.3693.9023-1.78383.59450.03870.20830.1805-0.1380.03410.36950.093-0.087-0.0810.13320.0097-0.06950.1481-0.04480.2885-4.1857-14.0347-1.7251
33.01660.6692-0.77392.1608-0.86212.7397-0.5255-2.0066-0.66930.01880.3975-0.14960.2265-0.08090.08780.27840.0274-0.11390.79760.210.409712.6922-6.507330.0273
41.26810.0589-0.4240.70740.47831.7073-0.327-1.42391.17380.0757-0.34260.5246-0.2679-0.26030.26350.33990.0742-0.180.7754-0.39730.8236-1.42592.766729.1607
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain H and resseq 1:128)
2X-RAY DIFFRACTION2(chain L and resseq 1:127)
3X-RAY DIFFRACTION3(chain H and resseq 129:224)
4X-RAY DIFFRACTION4(chain L and resseq 128:227)

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