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- PDB-6bfq: The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies -

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Basic information

Entry
Database: PDB / ID: 6bfq
TitleThe mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies
Components
  • Fab Heavy chainFragment antigen-binding
  • Fab Light ChainFragment antigen-binding
  • Granulocyte-macrophage colony-stimulating factor
KeywordsIMMUNE SYSTEM / cytokine-Fab complex / Pulmonary Alveolar Proteinosis / receptor assembly / autoantibodies
Function / homology
Function and homology information


granulocyte macrophage colony-stimulating factor receptor binding / histamine secretion / neutrophil differentiation / response to silicon dioxide / epithelial fluid transport / positive regulation of interleukin-23 production / regulation of circadian sleep/wake cycle, sleep / dendritic cell differentiation / response to fluid shear stress / positive regulation of macrophage derived foam cell differentiation ...granulocyte macrophage colony-stimulating factor receptor binding / histamine secretion / neutrophil differentiation / response to silicon dioxide / epithelial fluid transport / positive regulation of interleukin-23 production / regulation of circadian sleep/wake cycle, sleep / dendritic cell differentiation / response to fluid shear stress / positive regulation of macrophage derived foam cell differentiation / myeloid dendritic cell differentiation / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / myeloid cell differentiation / positive regulation of leukocyte proliferation / cellular response to granulocyte macrophage colony-stimulating factor stimulus / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / positive regulation of podosome assembly / Interleukin-10 signaling / cell surface receptor signaling pathway via JAK-STAT / monocyte differentiation / macrophage differentiation / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Interleukin-3, Interleukin-5 and GM-CSF signaling / embryonic placenta development / Interleukin receptor SHC signaling / positive regulation of tyrosine phosphorylation of STAT protein / cytokine activity / growth factor activity / RAF/MAP kinase cascade / cellular response to lipopolysaccharide / cell population proliferation / positive regulation of cell migration / immune response / intracellular membrane-bounded organelle / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / positive regulation of gene expression / extracellular space / 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) / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Immunoglobulins / Up-down Bundle / Immunoglobulin-like ...Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor signature. / Granulocyte-macrophage colony-simulating factor (GM-CSF) / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Granulocyte-macrophage colony-stimulating factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 Å
AuthorsDhagat, U. / Hercus, T.R. / Broughton, S.E. / Nero, T.L. / Lopez, A.F. / Parker, M.W.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia) Australia
Citation
Journal: MAbs / Year: 2018
Title: The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeutic opportunities.
Authors: Dhagat, U. / Hercus, T.R. / Broughton, S.E. / Nero, T.L. / Cheung Tung Shing, K.S. / Barry, E.F. / Thomson, C.A. / Bryson, S. / Pai, E.F. / McClure, B.J. / Schrader, J.W. / Lopez, A.F. / Parker, M.W.
#1: Journal: To Be Published
Title: Structure of a cytokine-Fab complex
Authors: Dhagat, U. / Hercus, T. / Broughton, S.B. / Nero, T.N. / Lopez, A.F. / Schrader, J.W. / Parker, M.W.
History
DepositionOct 26, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 12, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 3, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Fab Heavy chain
L: Fab Light Chain
A: Fab Heavy chain
B: Fab Light Chain
C: Fab Heavy chain
D: Fab Light Chain
E: Fab Heavy chain
F: Fab Light Chain
G: Granulocyte-macrophage colony-stimulating factor
J: Granulocyte-macrophage colony-stimulating factor
I: Granulocyte-macrophage colony-stimulating factor
K: Granulocyte-macrophage colony-stimulating factor


Theoretical massNumber of molelcules
Total (without water)247,45812
Polymers247,45812
Non-polymers00
Water3,477193
1
H: Fab Heavy chain
L: Fab Light Chain
K: Granulocyte-macrophage colony-stimulating factor


Theoretical massNumber of molelcules
Total (without water)61,8643
Polymers61,8643
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-24 kcal/mol
Surface area24160 Å2
MethodPISA
2
A: Fab Heavy chain
B: Fab Light Chain
I: Granulocyte-macrophage colony-stimulating factor


Theoretical massNumber of molelcules
Total (without water)61,8643
Polymers61,8643
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-23 kcal/mol
Surface area23720 Å2
MethodPISA
3
C: Fab Heavy chain
D: Fab Light Chain
G: Granulocyte-macrophage colony-stimulating factor


Theoretical massNumber of molelcules
Total (without water)61,8643
Polymers61,8643
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5000 Å2
ΔGint-27 kcal/mol
Surface area23980 Å2
MethodPISA
4
E: Fab Heavy chain
F: Fab Light Chain
J: Granulocyte-macrophage colony-stimulating factor


Theoretical massNumber of molelcules
Total (without water)61,8643
Polymers61,8643
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4990 Å2
ΔGint-23 kcal/mol
Surface area24090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.437, 100.535, 101.866
Angle α, β, γ (deg.)91.170, 117.960, 108.650
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11H
21A
12H
22C
13H
23E
14L
24B
15L
25D
16L
26F
17A
27C
18A
28E
19B
29D
110B
210F
111C
211E
112D
212F
113G
213J
114G
214I
115G
215K
116J
216I
117J
217K
118I
218K

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALALYSLYSHA2 - 2132 - 216
21ALAALALYSLYSAC2 - 2132 - 216
12ALAALALYSLYSHA2 - 2132 - 216
22ALAALALYSLYSCE2 - 2132 - 216
13ALAALALYSLYSHA2 - 2132 - 216
23ALAALALYSLYSEG2 - 2132 - 216
14ASPASPGLYGLYLB2 - 2132 - 213
24ASPASPGLYGLYBD2 - 2132 - 213
15ASPASPARGARGLB2 - 2122 - 212
25ASPASPARGARGDF2 - 2122 - 212
16ASPASPARGARGLB2 - 2122 - 212
26ASPASPARGARGFH2 - 2122 - 212
17ALAALALYSLYSAC2 - 2132 - 216
27ALAALALYSLYSCE2 - 2132 - 216
18ALAALALYSLYSAC2 - 2132 - 216
28ALAALALYSLYSEG2 - 2132 - 216
19ASPASPARGARGBD2 - 2122 - 212
29ASPASPARGARGDF2 - 2122 - 212
110ASPASPARGARGBD2 - 2122 - 212
210ASPASPARGARGFH2 - 2122 - 212
111ALAALALYSLYSCE2 - 2132 - 216
211ALAALALYSLYSEG2 - 2132 - 216
112ASPASPGLUGLUDF2 - 2142 - 214
212ASPASPGLUGLUFH2 - 2142 - 214
113ARGARGGLUGLUGI23 - 12323 - 123
213ARGARGGLUGLUJJ23 - 12323 - 123
114ARGARGGLUGLUGI23 - 12323 - 123
214ARGARGGLUGLUIK23 - 12323 - 123
115ARGARGGLUGLUGI23 - 12323 - 123
215ARGARGGLUGLUKL23 - 12323 - 123
116ARGARGGLUGLUJJ23 - 12323 - 123
216ARGARGGLUGLUIK23 - 12323 - 123
117ILEILEGLUGLUJJ19 - 12319 - 123
217ILEILEGLUGLUKL19 - 12319 - 123
118ARGARGGLUGLUIK23 - 12323 - 123
218ARGARGGLUGLUKL23 - 12323 - 123

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

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Components

#1: Antibody
Fab Heavy chain / Fragment antigen-binding


Mass: 23877.707 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#2: Antibody
Fab Light Chain / Fragment antigen-binding


Mass: 23494.256 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Protein
Granulocyte-macrophage colony-stimulating factor / / GM-CSF / Colony-stimulating factor / CSF / Molgramostin / Sargramostim


Mass: 14492.495 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF2, GMCSF / Production host: Escherichia coli (E. coli) / References: UniProt: P04141
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 193 / Source method: isolated from a natural source / Formula: H2O

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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: 3.24 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 283.15 K / Method: vapor diffusion, hanging drop
Details: 0.16 M Calcium acetate, 14.4% PEG8000, 0.08 M Sodium Cacodylate pH 6.5 and 20% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.954 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 8, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.954 Å / Relative weight: 1
ReflectionResolution: 2.6→50.01 Å / Num. obs: 94668 / % possible obs: 98.7 % / Redundancy: 4.1 % / CC1/2: 0.967 / Rmerge(I) obs: 0.246 / Rpim(I) all: 0.134 / Rrim(I) all: 0.281 / Net I/σ(I): 39
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsCC1/2Rpim(I) all% possible allRmerge(I) obsRrim(I) all
2.6-2.642.744710.3440.82893.4
14.22-46.634.45530.990.05195.70.0970.11

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.44
Highest resolutionLowest resolution
Rotation45.11 Å2.91 Å

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Processing

Software
NameVersionClassification
Aimless0.5.4data scaling
MOLREPphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JIX

2jix


Resolution: 2.6→50.01 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.892 / SU B: 13.724 / SU ML: 0.272 / SU R Cruickshank DPI: 0.4957 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.498 / ESU R Free: 0.299
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2644 4789 5.1 %RANDOM
Rwork0.2303 ---
obs0.232 89368 98.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 147.8 Å2 / Biso mean: 44.751 Å2 / Biso min: 13.05 Å2
Baniso -1Baniso -2Baniso -3
1--1.1 Å20.38 Å20.54 Å2
2--1.08 Å2-0.77 Å2
3----0.27 Å2
Refinement stepCycle: final / Resolution: 2.6→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16012 0 0 193 16205
Biso mean---29.23 -
Num. residues----2086
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0216408
X-RAY DIFFRACTIONr_bond_other_d0.0060.0214890
X-RAY DIFFRACTIONr_angle_refined_deg1.6751.96222326
X-RAY DIFFRACTIONr_angle_other_deg1.004334767
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.07952071
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.06424.33649
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.919152709
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9861576
X-RAY DIFFRACTIONr_chiral_restr0.0940.22553
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02118085
X-RAY DIFFRACTIONr_gen_planes_other0.0020.023195
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11H122700.05
12A122700.05
21H122020.07
22C122020.07
31H122940.04
32E122940.04
41L124740.07
42B124740.07
51L125220.06
52D125220.06
61L125820.07
62F125820.07
71A121720.06
72C121720.06
81A121240.06
82E121240.06
91B125580.07
92D125580.07
101B124660.07
102F124660.07
111C121360.07
112E121360.07
121D125640.08
122F125640.08
131G53220.11
132J53220.11
141G53720.1
142I53720.1
151G52900.12
152K52900.12
161J54820.09
162I54820.09
171J59580.1
172K59580.1
181I54060.1
182K54060.1
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.413 326 -
Rwork0.377 6503 -
all-6829 -
obs--97.11 %

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