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- PDB-9gjv: Fab fragment of an antibody that recognises alpha-1 antitrypsin -

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Basic information

Entry
Database: PDB / ID: 9gjv
TitleFab fragment of an antibody that recognises alpha-1 antitrypsin
Components
  • FAB 9C5 heavy chain
  • FAB 9C5 light chain
KeywordsPROTEIN BINDING / Fab fragment / antitrypsin / serpin / antibody
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsAldobiyan, I. / Lomas, D.A. / Irving, J.A.
Funding support United Kingdom, United States, 3items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/V034243/1 United Kingdom
Other governmentNIHR investigator award to DAL United Kingdom
Other privateAlpha-1 Foundation to JAI (1036784) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: The mechanism of pathogenic α-antitrypsin aggregation in the human liver.
Authors: Ibrahim Aldobiyan / Emma L K Elliston / Narinder Heyer-Chauhan / Stefan T Arold / Lingyun Zhao / Brandon Huntington / Sarah M Lowen / Elena V Orlova / James A Irving / David A Lomas /
Abstract: Originating 2 to 3 millennia ago in a Scandinavian population, the SERPINA1 Z allele (Glu342Lys) is present in up to 2.5% of populations of Northern European descent and accounts for 95% of severe α- ...Originating 2 to 3 millennia ago in a Scandinavian population, the SERPINA1 Z allele (Glu342Lys) is present in up to 2.5% of populations of Northern European descent and accounts for 95% of severe α-antitrypsin deficiency. The α-antitrypsin Z variant self-assembles into polymer chains that deposit within hepatocytes, predisposing to liver disease. Here, the 4.0Å subunit structure of polymers isolated directly from human liver tissue has been determined using cryoelectron microscopy. Challenges of flexibility, small subunit size, heterogeneous length, and preferred orientations were mitigated using antibody Fab domains and sample preparation strategies. This structure demonstrates that the formation of polymers in vivo involves self-incorporation of an exposed structural element (the reactive center loop) as an additional β-strand into the central β-sheet of α-antitrypsin and displacement of a C-terminal region from one subunit with incorporation into the next. Unlike amyloid aggregation, this well-folded structure partially recapitulates a conformation adopted during normal function of the protein. These perturbations to the constituent α-antitrypsin subunits of human tissue-derived polymers are consistent with a pronounced stability, their tendency toward long-chain forms, the ability of a subset to undergo canonical secretion, and the action of a class of small molecules that block polymerization in vivo.
History
DepositionAug 22, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _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 9C5 heavy chain
L: FAB 9C5 light chain


Theoretical massNumber of molelcules
Total (without water)47,1642
Polymers47,1642
Non-polymers00
Water1,22568
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3480 Å2
ΔGint-25 kcal/mol
Surface area19170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.766, 58.618, 158.839
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody FAB 9C5 heavy chain


Mass: 23454.240 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#2: Antibody FAB 9C5 light chain


Mass: 23709.357 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.06 Å3/Da / Density % sol: 40.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100 mM HEPES free acid, pH 7.5, 200 mM Magnesium chloride, 25 (%w/v) PEG 3350 Cryoprotectant: 10% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryostream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.8856 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: May 5, 2023 / Details: Toroidal mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8856 Å / Relative weight: 1
ReflectionResolution: 2.2→58.62 Å / Num. obs: 20062 / % possible obs: 98.2 % / Redundancy: 8.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.112 / Rpim(I) all: 0.04 / Rrim(I) all: 0.119 / Χ2: 0.99 / Net I/σ(I): 10.3 / Num. measured all: 163542
Reflection shellResolution: 2.2→2.27 Å / % possible obs: 99.2 % / Redundancy: 8.4 % / Rmerge(I) obs: 1.802 / Num. measured all: 14488 / Num. unique obs: 1721 / CC1/2: 0.475 / Rpim(I) all: 0.619 / Rrim(I) all: 1.913 / Χ2: 1.02 / Net I/σ(I) obs: 1.2

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimless0.7.13data scaling
XDSdata reduction
PHASER2.82phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→54.99 Å / SU ML: 0.42 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2622 1003 5.01 %
Rwork0.2442 --
obs0.2451 20032 97.38 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→54.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3172 0 0 68 3240
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023347
X-RAY DIFFRACTIONf_angle_d0.5054613
X-RAY DIFFRACTIONf_dihedral_angle_d12.3141157
X-RAY DIFFRACTIONf_chiral_restr0.042540
X-RAY DIFFRACTIONf_plane_restr0.004603
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.320.4391440.36052692X-RAY DIFFRACTION99
2.32-2.460.38951290.36022714X-RAY DIFFRACTION99
2.46-2.650.41211450.36752696X-RAY DIFFRACTION98
2.65-2.920.32611550.30842684X-RAY DIFFRACTION98
2.92-3.340.30171380.27392690X-RAY DIFFRACTION97
3.34-4.210.25271430.22482748X-RAY DIFFRACTION97
4.21-54.990.18951490.18982805X-RAY DIFFRACTION95
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)
11.03191.23710.36714.9756-1.94994.47020.01460.75450.21840.522-0.329-1.0782-0.51041.79560.31770.4286-0.016-0.01380.8396-0.06670.769712.9808-2.5946-28.0505
21.10970.23941.04897.6631-2.21248.28920.08110.5711-0.5441-0.15080.1903-1.28141.03710.9362-0.29560.77310.217-0.16590.7383-0.22990.77229.4348-12.2091-24.9364
32.6741-1.56650.61755.3335-0.44873.5413-0.0256-0.23810.18140.32060.2725-0.89080.34270.602-0.14550.37960.0868-0.03770.5666-0.13150.50984.9666-3.649-27.9924
45.02230.02132.13994.8066-1.95281.75960.0346-0.0090.36180.011-0.9257-0.0897-1.2843-0.91340.85830.49460.1068-0.04020.43580.05220.4481-15.87528.6082-22.7433
53.5251-2.4433-2.40775.45471.4536.8020.3382-0.25770.5822-0.1021-0.0164-0.1515-0.61250.1178-0.24430.2545-0.02930.06470.3348-0.0430.4448-7.285620.8316-25.2523
64.33910.55021.54552.9345-0.99735.931-0.1079-0.5538-0.07751.8110.4475-0.54990.6510.2398-0.35181.22670.2203-0.23960.5624-0.10180.57482.4431-7.9519-5.0646
75.8211-3.96111.4076.7506-1.0696.90180.00290.1857-0.05120.0164-0.36660.57440.2942-0.65540.24570.2895-0.00530.05660.5309-0.16850.4971-21.825417.5495-18.9952
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'H' and (resid 1 through 32 )
2X-RAY DIFFRACTION2chain 'H' and (resid 33 through 75 )
3X-RAY DIFFRACTION3chain 'H' and (resid 76 through 118 )
4X-RAY DIFFRACTION4chain 'H' and (resid 119 through 133 )
5X-RAY DIFFRACTION5chain 'H' and (resid 134 through 214 )
6X-RAY DIFFRACTION6chain 'L' and (resid 1 through 102 )
7X-RAY DIFFRACTION7chain 'L' and (resid 103 through 214 )

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