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- PDB-6qu9: Fab fragment of an antibody that inhibits polymerisation of alpha... -

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Basic information

Entry
Database: PDB / ID: 6qu9
TitleFab fragment of an antibody that inhibits polymerisation of alpha-1-antitrypsin
Components
  • FAB 4B12 heavy chain
  • FAB 4B12 light chain
KeywordsPROTEIN BINDING / Alpha-1 antitrypsin / Z variant / polymers / protein aggregation / monoclonal antibody / Fab fragment / COPD / protease inhibitor / glycoprotein / deficiency
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsJagger, A.M. / Heyer-Chauhan, N. / Lomas, D.A. / Irving, J.A.
Funding support United Kingdom, United States, 3items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/N024842/1 United Kingdom
Other governmentUCLH/NIHR Biomedical Research Centre United Kingdom
Other privateAlpha-1 Foundation project grant to J. Irving United States
CitationJournal: Sci Adv / Year: 2020
Title: The structural basis for Z α-antitrypsin polymerization in the liver.
Authors: Sarah V Faull / Emma L K Elliston / Bibek Gooptu / Alistair M Jagger / Ibrahim Aldobiyan / Adam Redzej / Magd Badaoui / Nina Heyer-Chauhan / S Tamir Rashid / Gary M Reynolds / David H Adams ...Authors: Sarah V Faull / Emma L K Elliston / Bibek Gooptu / Alistair M Jagger / Ibrahim Aldobiyan / Adam Redzej / Magd Badaoui / Nina Heyer-Chauhan / S Tamir Rashid / Gary M Reynolds / David H Adams / Elena Miranda / Elena V Orlova / James A Irving / David A Lomas /
Abstract: The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α-Antitrypsin deficiency is the archetypal ...The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α-antitrypsin as "polymer" chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α-antitrypsin.
History
DepositionFeb 26, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: FAB 4B12 heavy chain
L: FAB 4B12 light chain
A: FAB 4B12 heavy chain
B: FAB 4B12 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,1169
Polymers93,7164
Non-polymers3995
Water7,656425
1
H: FAB 4B12 heavy chain
L: FAB 4B12 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,9774
Polymers46,8582
Non-polymers1192
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4000 Å2
ΔGint-47 kcal/mol
Surface area18960 Å2
MethodPISA
2
A: FAB 4B12 heavy chain
B: FAB 4B12 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,1385
Polymers46,8582
Non-polymers2803
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3530 Å2
ΔGint-38 kcal/mol
Surface area18390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.268, 105.102, 105.128
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Antibody , 2 types, 4 molecules HALB

#1: Antibody FAB 4B12 heavy chain


Mass: 23374.119 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Cell line: Hybridoma / Organ: Spleen / Variant: BALB/c
#2: Antibody FAB 4B12 light chain


Mass: 23484.051 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Cell line: Hybridoma / Organ: Spleen / Variant: BALB/c

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Non-polymers , 4 types, 430 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 425 / 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: 2.35 Å3/Da / Density % sol: 47.65 % / Description: Plate
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.1M Bis-Tris pH 5.5, 25% PEG 3350, 0.2M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Cryostream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 21, 2018 / Details: Vertical CRL / horizontal eliptical mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.9→105.1 Å / Num. obs: 69862 / % possible obs: 99.9 % / Redundancy: 6.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.082 / Rpim(I) all: 0.036 / Rrim(I) all: 0.09 / Χ2: 0.83 / Net I/av σ(I): 9.8 / Net I/σ(I): 9.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.946.50.8451.644690.7920.3590.9190.5799.9
9.11-105.15.20.05220.97460.9960.0250.0580.6999.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.74 Å29.5 Å
Translation3.74 Å29.5 Å

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Processing

Software
NameVersionClassification
PHENIX1.14-3260refinement
XDS20180126data reduction
Aimless0.6.2data scaling
PHASER2.8.1phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Model generated using RosettaAntibody protocol

Resolution: 1.9→63.287 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.94
RfactorNum. reflection% reflection
Rfree0.2328 3388 4.86 %
Rwork0.2019 --
obs0.2034 69773 99.9 %
Solvent computationShrinkage radii: 1 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 100.66 Å2 / Biso mean: 48.0283 Å2 / Biso min: 26.16 Å2
Refinement stepCycle: final / Resolution: 1.9→63.287 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6378 0 23 425 6826
Biso mean--53.15 49.28 -
Num. residues----848
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.9-1.92710.31671460.29992716
1.9271-1.95590.32151300.28742779
1.9559-1.98650.33551390.27772721
1.9865-2.0190.32921560.27222685
2.019-2.05390.32551540.26282738
2.0539-2.09120.28451190.26712769
2.0912-2.13140.31971140.25212758
2.1314-2.17490.24771220.24812719
2.1749-2.22220.28791300.242772
2.2222-2.27390.27521410.23632746
2.2739-2.33080.27991430.23952741
2.3308-2.39380.27581510.23932771
2.3938-2.46430.25331440.24062705
2.4643-2.54380.2791460.23722750
2.5438-2.63470.23541530.23442786
2.6347-2.74020.26351460.23572728
2.7402-2.86490.28311210.23512779
2.8649-3.0160.27731620.22842768
3.016-3.20490.28121410.21022753
3.2049-3.45240.22281540.2092792
3.4524-3.79980.24251640.18522756
3.7998-4.34950.18441070.16782857
4.3495-5.47940.15961530.14822841
5.4794-63.2870.19721520.17822955

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