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Basic information

Entry
Database: PDB / ID: 5bvp
TitleThe molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1beta
Components
  • Canakinumab Fab light-chain
  • Interleukin-1 beta
  • canakinumab Fab heavy-chain
KeywordsIMMUNE SYSTEM / immunoglobulin / Fab / cytokine / beta trefoil
Function / homology
Function and homology information


positive regulation of T cell mediated immunity / positive regulation of cell adhesion molecule production / negative regulation of adiponectin secretion / monocyte aggregation / negative regulation of lipid metabolic process / smooth muscle adaptation / positive regulation of lipid catabolic process / negative regulation of D-glucose transmembrane transport / regulation of nitric-oxide synthase activity / hyaluronan biosynthetic process ...positive regulation of T cell mediated immunity / positive regulation of cell adhesion molecule production / negative regulation of adiponectin secretion / monocyte aggregation / negative regulation of lipid metabolic process / smooth muscle adaptation / positive regulation of lipid catabolic process / negative regulation of D-glucose transmembrane transport / regulation of nitric-oxide synthase activity / hyaluronan biosynthetic process / positive regulation of T-helper 1 cell cytokine production / positive regulation of complement activation / : / cellular response to interleukin-17 / positive regulation of RNA biosynthetic process / positive regulation of tight junction disassembly / positive regulation of prostaglandin biosynthetic process / negative regulation of gap junction assembly / positive regulation of immature T cell proliferation in thymus / vascular endothelial growth factor production / positive regulation of prostaglandin secretion / positive regulation of neuroinflammatory response / positive regulation of platelet-derived growth factor receptor signaling pathway / regulation of defense response to virus by host / fever generation / positive regulation of fever generation / regulation of establishment of endothelial barrier / CLEC7A/inflammasome pathway / Interleukin-1 processing / negative regulation of synaptic transmission / response to carbohydrate / positive regulation of monocyte chemotactic protein-1 production / interleukin-1 receptor binding / positive regulation of heterotypic cell-cell adhesion / positive regulation of macrophage derived foam cell differentiation / positive regulation of p38MAPK cascade / positive regulation of membrane protein ectodomain proteolysis / positive regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of granulocyte macrophage colony-stimulating factor production / regulation of canonical NF-kappaB signal transduction / interleukin-1-mediated signaling pathway / response to ATP / Interleukin-10 signaling / positive regulation of cell division / regulation of neurogenesis / positive regulation of vascular endothelial growth factor production / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of MAP kinase activity / Pyroptosis / ectopic germ cell programmed cell death / negative regulation of lipid catabolic process / regulation of ERK1 and ERK2 cascade / Purinergic signaling in leishmaniasis infection / positive regulation of epithelial to mesenchymal transition / positive regulation of T cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / JNK cascade / positive regulation of glial cell proliferation / neutrophil chemotaxis / embryo implantation / negative regulation of insulin receptor signaling pathway / positive regulation of interleukin-2 production / response to interleukin-1 / positive regulation of mitotic nuclear division / regulation of insulin secretion / secretory granule / positive regulation of protein export from nucleus / cytokine activity / positive regulation of interleukin-8 production / astrocyte activation / positive regulation of JNK cascade / positive regulation of non-canonical NF-kappaB signal transduction / cytokine-mediated signaling pathway / negative regulation of neurogenesis / positive regulation of interleukin-6 production / positive regulation of type II interferon production / Interleukin-1 signaling / cellular response to mechanical stimulus / positive regulation of inflammatory response / positive regulation of angiogenesis / positive regulation of NF-kappaB transcription factor activity / positive regulation of nitric oxide biosynthetic process / integrin binding / cellular response to xenobiotic stimulus / cell-cell signaling / cellular response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / response to lipopolysaccharide / positive regulation of canonical NF-kappaB signal transduction / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / defense response to Gram-positive bacterium / immune response / positive regulation of cell migration / inflammatory response / protein domain specific binding / negative regulation of cell population proliferation / apoptotic process
Similarity search - Function
Interleukin-1 propeptide / Interleukin-1 propeptide / Interleukin-1 conserved site / Interleukin-1 signature. / Interleukin-1 homologues / Interleukin-1 family / Interleukin-1 / 18 / Cytokine IL1/FGF / Trefoil (Acidic Fibroblast Growth Factor, subunit A) - #50 / Trefoil (Acidic Fibroblast Growth Factor, subunit A) ...Interleukin-1 propeptide / Interleukin-1 propeptide / Interleukin-1 conserved site / Interleukin-1 signature. / Interleukin-1 homologues / Interleukin-1 family / Interleukin-1 / 18 / Cytokine IL1/FGF / Trefoil (Acidic Fibroblast Growth Factor, subunit A) - #50 / Trefoil (Acidic Fibroblast Growth Factor, subunit A) / Trefoil / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsRondeau, J.M.
CitationJournal: Mabs / Year: 2015
Title: The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1 beta.
Authors: Rondeau, J.M. / Ramage, P. / Zurini, M. / Gram, H.
History
DepositionJun 5, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 2, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2015Group: Database references
Revision 1.2Oct 28, 2015Group: Database references
Revision 2.0Mar 11, 2020Group: Data collection / Polymer sequence / Category: diffrn_radiation_wavelength / entity_poly / Item: _entity_poly.pdbx_seq_one_letter_code_can
Revision 2.1Jan 10, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: canakinumab Fab heavy-chain
I: Interleukin-1 beta
L: Canakinumab Fab light-chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0285
Polymers64,9573
Non-polymers712
Water4,576254
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5800 Å2
ΔGint-44 kcal/mol
Surface area26440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.928, 56.285, 191.704
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody canakinumab Fab heavy-chain / ILARIS Fab


Mass: 24179.053 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell (production host): Myeloma / Cell line (production host): SP2/0 / Production host: Mus musculus (house mouse)
#2: Protein Interleukin-1 beta / IL-1 beta / Catabolin


Mass: 17395.832 Da / Num. of mol.: 1 / Fragment: Fab heavy-chain, UNP residues 117-269
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL1B, IL1F2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01584
#3: Antibody Canakinumab Fab light-chain / ILARIS Fab


Mass: 23381.908 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell (production host): Myeloma / Cell line (production host): SP2/0 / Production host: Mus musculus (house mouse)
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 254 / 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: 2.11 Å3/Da / Density % sol: 41.84 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.09M MIB BUFFER PH 5.0, 22.5% PEG 1,500, 0.01M TRIS-HCL PH 8.5, 0.4M LICL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Apr 26, 2006
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionRedundancy: 7 % / Number: 199762 / Rmerge(I) obs: 0.038 / Χ2: 0.99 / D res high: 2.2 Å / D res low: 100 Å / Num. obs: 28731 / % possible obs: 99
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
4.7410010.0240.9726.7
3.764.7410.031.1776.6
3.293.7610.0371.2737
2.993.2910.0451.2027.1
2.772.9910.0581.1017.1
2.612.7710.0720.997.1
2.482.6110.0950.8947.1
2.372.4810.120.7997.1
2.282.3710.1510.7597.1
2.22.2810.1790.7216.7
ReflectionResolution: 2.2→100 Å / Num. obs: 28731 / % possible obs: 99 % / Redundancy: 7 % / Biso Wilson estimate: 47 Å2 / Rmerge(I) obs: 0.038 / Χ2: 0.989 / Net I/av σ(I): 44.445 / Net I/σ(I): 24.7 / Num. measured all: 199762
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
2.2-2.286.70.1797.328160.72199.8
2.28-2.377.10.15128660.759100
2.37-2.487.10.1228470.79999.9
2.48-2.617.10.09528500.894100
2.61-2.777.10.07228510.9999.9
2.77-2.997.10.05828851.10199.7
2.99-3.297.10.04528591.20299.2
3.29-3.7670.03728901.27398.7
3.76-4.746.60.0328421.17796.2
4.74-1006.70.02430250.97296.9

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Processing

Software
NameVersionClassification
HKL-20001.98.5data reduction
SCALEPACK1.98.5data scaling
BUSTER-TNTBUSTER 2.11.2refinement
PDB_EXTRACT3.15data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2I1B

2i1b


Resolution: 2.2→49.22 Å / Cor.coef. Fo:Fc: 0.9507 / Cor.coef. Fo:Fc free: 0.9297 / SU R Cruickshank DPI: 0.291 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.314 / SU Rfree Blow DPI: 0.21 / SU Rfree Cruickshank DPI: 0.207
RfactorNum. reflection% reflectionSelection details
Rfree0.2311 1459 5.1 %RANDOM
Rwork0.1879 ---
obs0.1901 28599 99.03 %-
Displacement parametersBiso max: 166.02 Å2 / Biso mean: 54.51 Å2 / Biso min: 17.51 Å2
Baniso -1Baniso -2Baniso -3
1--0.3938 Å20 Å20 Å2
2---4.5599 Å20 Å2
3---4.9537 Å2
Refine analyzeLuzzati coordinate error obs: 0.346 Å
Refinement stepCycle: final / Resolution: 2.2→49.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4489 0 2 254 4745
Biso mean--59.18 45.82 -
Num. residues----582
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1557SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes112HARMONIC2
X-RAY DIFFRACTIONt_gen_planes660HARMONIC5
X-RAY DIFFRACTIONt_it4593HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion593SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5191SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4593HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6231HARMONIC21.18
X-RAY DIFFRACTIONt_omega_torsion3.71
X-RAY DIFFRACTIONt_other_torsion17.8
LS refinement shellResolution: 2.2→2.28 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.3362 156 5.26 %
Rwork0.22 2811 -
all0.2259 2967 -
obs--99.03 %
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)DetailsOrigin x (Å)Origin y (Å)Origin z (Å)
11.4614-0.2083-2.06770.1168-0.42934.30330.3012-0.39740.19340.2239-0.1763-0.0823-0.90760.6054-0.12490.013-0.1847-0.0113-0.0777-0.0983-0.1106canakinumab Heavy-chain5.1865-6.3075-16.0422
22.81020.1746-0.8192.2102-1.27223.5119-0.02940.2631-0.2526-0.562-0.2505-0.17690.52010.20530.2799-0.0450.12370.0764-0.10240.0356-0.0993Interleukin-1 beta16.3024-17.6275-59.3426
30.7601-0.2245-0.58660-0.30823.82260.08150.0350.1530.1441-0.0171-0.0297-0.7201-0.7081-0.0644-0.08360.09680.0127-0.06-0.0667-0.1232Canakinumab light-chain-11.499-8.9867-21.0785
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ H|* }H - L1 - 220
2X-RAY DIFFRACTION2{ I|* }I3 - 153
3X-RAY DIFFRACTION3{ L|* }L1 - 213

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