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- PDB-9jkr: human GM-CSF with Fabs from autoantibodies, F1 and C. -

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Basic information

Entry
Database: PDB / ID: 9jkr
Titlehuman GM-CSF with Fabs from autoantibodies, F1 and C.
Components
  • Fab region of C antibody heavy chain
  • Fab region of C antibody light chain
  • Fab region of F1 antibody heavy chain
  • Fab region of F1 antibody light chain
  • Granulocyte-macrophage colony-stimulating factor
KeywordsIMMUNE SYSTEM / Autoimmune pulmonary alveolar proteinosis / autoantibody
Function / homology
Function and homology information


granulocyte macrophage colony-stimulating factor receptor binding / histamine secretion / response to silicon dioxide / epithelial fluid transport / positive regulation of interleukin-23 production / myeloid dendritic cell differentiation / positive regulation of podosome assembly / dendritic cell differentiation / regulation of circadian sleep/wake cycle, sleep / myeloid cell differentiation ...granulocyte macrophage colony-stimulating factor receptor binding / histamine secretion / response to silicon dioxide / epithelial fluid transport / positive regulation of interleukin-23 production / myeloid dendritic cell differentiation / positive regulation of podosome assembly / dendritic cell differentiation / regulation of circadian sleep/wake cycle, sleep / myeloid cell differentiation / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / response to fluid shear stress / positive regulation of leukocyte proliferation / positive regulation of macrophage derived foam cell differentiation / cell surface receptor signaling pathway via STAT / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Interleukin-10 signaling / macrophage differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / cytokine activity / growth factor activity / cellular response to lipopolysaccharide / RAF/MAP kinase cascade / positive regulation of cell migration / immune response / negative regulation of DNA-templated transcription / positive regulation of gene expression / positive regulation of cell population proliferation / extracellular region / plasma membrane
Similarity search - Function
Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor signature. / Granulocyte-macrophage colony-simulating factor (GM-CSF) / Four-helical cytokine-like, core
Similarity search - Domain/homology
Granulocyte-macrophage colony-stimulating factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsKishikawa, J. / Kato, T. / Kurosaki, T. / Inoue, T.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)23K07625 Japan
Other private26-2-40 Japan
CitationJournal: Nat Commun / Year: 2026
Title: Affinity- and epitope-dependent pathogenicity of GM-CSF autoantibodies in patients with autoimmune pulmonary alveolar proteinosis.
Authors: Shinji Futami / Chie Kawai / Jun-Ichi Kishikawa / Masaki Hirose / Hiroshi Kida / Po-Hung Wang / Kazuo Yamashita / Fumihiko Ishikawa / Takayuki Kato / Yoshikazu Inoue / Atsushi Kumanogoh / ...Authors: Shinji Futami / Chie Kawai / Jun-Ichi Kishikawa / Masaki Hirose / Hiroshi Kida / Po-Hung Wang / Kazuo Yamashita / Fumihiko Ishikawa / Takayuki Kato / Yoshikazu Inoue / Atsushi Kumanogoh / Tomohiro Kurosaki / Takeshi Inoue /
Abstract: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by autoantibodies targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). Although serum GM-CSF ...Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by autoantibodies targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). Although serum GM-CSF autoantibody levels are markedly increased in aPAP patients, total antibody titer does not correlate with disease severity. Here, we characterize 186 monoclonal anti-GM-CSF autoantibodies derived from GM-CSF-specific B cells in 28 aPAP patients with varying disease severity, including three longitudinal cohorts, to determine whether epitope specificity and affinity of the autoantibodies contribute to disease pathophysiology. We classify these antibodies into two groups based on their epitopes: class 1 (targeting A, BD, or D epitopes) and class 2 (targeting B or C epitopes). In class 1 antibodies, affinity strongly correlates with neutralization activity, whereas this relationship is weak or absent in class 2 antibodies. High-affinity class 1 antibodies are present at higher levels in patients with more severe disease and are sufficient to induce PAP symptoms in a humanized mouse model. Thus, these findings identify epitope specificity and affinity as key determinants of pathogenicity and provide a mechanistic framework for understanding why total serum autoantibody levels fail to reflect disease severity in aPAP.
History
DepositionSep 17, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 25, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fab region of F1 antibody heavy chain
B: Fab region of F1 antibody light chain
C: Fab region of C antibody heavy chain
D: Fab region of C antibody light chain
I: Granulocyte-macrophage colony-stimulating factor


Theoretical massNumber of molelcules
Total (without water)115,2945
Polymers115,2945
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody Fab region of F1 antibody heavy chain


Mass: 24706.588 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: C-terminal is His x6 tag for purification / Source: (gene. exp.) Homo sapiens (human) / Cell (production host): expi293 / Production host: Homo sapiens (human)
#2: Antibody Fab region of F1 antibody light chain


Mass: 23494.256 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell (production host): expi293 / Production host: Homo sapiens (human)
#3: Antibody Fab region of C antibody heavy chain


Mass: 25442.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: C terminal is His x6 tag for purification / Source: (gene. exp.) Homo sapiens (human) / Cell (production host): Expi293 / Production host: Homo sapiens (human)
#4: Antibody Fab region of C antibody light chain


Mass: 24459.273 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell (production host): Expi293 / Production host: Homo sapiens (human)
#5: Protein Granulocyte-macrophage colony-stimulating factor / GM-CSF / Colony-stimulating factor / CSF / Molgramostin / Sargramostim


Mass: 17191.404 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: 1-17 residues are signal peptides cleaved in purified protein. 145-159 residues are avi-tag for purification 160 is a linker 161-166 residues are his-tag for purification
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF2, GMCSF / Cell (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: P04141
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1the complex of human GM-CSF with Fabs from its autoantibodies, F1 and C.COMPLEXall0RECOMBINANT
2human GM-CSFCOMPLEX#51RECOMBINANT
3F1 autoantibody for human GM-CSFCOMPLEX#1-#21RECOMBINANT
4C autoantibody for human GM-CSFCOMPLEX#3-#41RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.12 MDaNO
210.015 MDaNO
3150 kDa/nmNO
4150 kDa/nmNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCellPlasmid
11Homo sapiens (human)9606Expi293pcDNA3.4
22Homo sapiens (human)9606Expi293pcDNA3.4
33Homo sapiens (human)9606Expi293pcDNA3.4
44Homo sapiens (human)9606Expi293pcDNA3.4
Buffer solutionpH: 7.5
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 0.054 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 3467
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2SerialEM4image acquisition
4cryoSPARC4.0.0CTF correction
7Cootmodel fitting
9cryoSPARC4.0.0initial Euler assignment
10cryoSPARC4.0.0final Euler assignment
11cryoSPARC4.0.0classification
12cryoSPARC4.0.03D reconstruction
13Servalcatmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 601878 / Details: topaz extraction
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 189815 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6BFQ

6bfq


Accession code: 6BFQ / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0054505
ELECTRON MICROSCOPYf_angle_d0.6576113
ELECTRON MICROSCOPYf_dihedral_angle_d9.7712672
ELECTRON MICROSCOPYf_chiral_restr0.045676
ELECTRON MICROSCOPYf_plane_restr0.004784

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