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- PDB-8dpv: The crystal structure of Interleukin-11, W147A mutant -

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Basic information

Entry
Database: PDB / ID: 8dpv
TitleThe crystal structure of Interleukin-11, W147A mutant
ComponentsInterleukin-11
KeywordsCYTOKINE / complex / IL-6 family cytokine
Function / homology
Function and homology information


interleukin-11 receptor binding / megakaryocyte differentiation / negative regulation of hormone secretion / interleukin-11-mediated signaling pathway / IL-6-type cytokine receptor ligand interactions / fat cell differentiation / B cell differentiation / cytokine activity / growth factor activity / positive regulation of peptidyl-tyrosine phosphorylation ...interleukin-11 receptor binding / megakaryocyte differentiation / negative regulation of hormone secretion / interleukin-11-mediated signaling pathway / IL-6-type cytokine receptor ligand interactions / fat cell differentiation / B cell differentiation / cytokine activity / growth factor activity / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of peptidyl-serine phosphorylation / cell population proliferation / positive regulation of MAPK cascade / positive regulation of cell population proliferation / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / cytoplasm
Similarity search - Function
Interleukin-11, mammalian / Interleukin-11 / Interleukin 11 / Four-helical cytokine-like, core
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsMetcalfe, R.D. / Griffin, M.D.W.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1147621 Australia
CitationJournal: Nat Commun / Year: 2023
Title: Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant.
Authors: Riley D Metcalfe / Eric Hanssen / Ka Yee Fung / Kaheina Aizel / Clara C Kosasih / Courtney O Zlatic / Larissa Doughty / Craig J Morton / Andrew P Leis / Michael W Parker / Paul R Gooley / ...Authors: Riley D Metcalfe / Eric Hanssen / Ka Yee Fung / Kaheina Aizel / Clara C Kosasih / Courtney O Zlatic / Larissa Doughty / Craig J Morton / Andrew P Leis / Michael W Parker / Paul R Gooley / Tracy L Putoczki / Michael D W Griffin /
Abstract: Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural ...Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
History
DepositionJul 17, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Interleukin-11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2903
Polymers18,1581
Non-polymers1322
Water1,964109
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.505, 133.996, 27.087
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-376-

HOH

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Components

#1: Protein Interleukin-11 / IL-11 / Adipogenesis inhibitory factor / AGIF


Mass: 18158.158 Da / Num. of mol.: 1 / Mutation: W147A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL11 / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P20809
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H2O
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: 1.92 Å3/Da / Density % sol: 36.08 % / Description: plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: PEG 3350, 200 mM ammonium sulphate, 100 mM Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: liquid nitrogen / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 20, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.48→44.67 Å / Num. obs: 24354 / % possible obs: 100 % / Redundancy: 12.9 % / Biso Wilson estimate: 23.39 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.034 / Rrim(I) all: 0.089 / Rsym value: 0.082 / Net I/σ(I): 12.9
Reflection shellResolution: 1.48→1.51 Å / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1182 / CC1/2: 0.59 / Rpim(I) all: 0.743 / Rrim(I) all: 2.003 / Rsym value: 1.859

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
Aimlessdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MHL

4mhl


Resolution: 1.48→37.01 Å / SU ML: 0.1497 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.2089
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2161 1216 5 %
Rwork0.1825 23080 -
obs0.1842 24296 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.47 Å2
Refinement stepCycle: LAST / Resolution: 1.48→37.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1278 0 6 109 1393
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01271343
X-RAY DIFFRACTIONf_angle_d1.28441840
X-RAY DIFFRACTIONf_chiral_restr0.0797218
X-RAY DIFFRACTIONf_plane_restr0.0092241
X-RAY DIFFRACTIONf_dihedral_angle_d20.1668518
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.48-1.540.27421400.272491X-RAY DIFFRACTION100
1.54-1.610.25051470.22982508X-RAY DIFFRACTION100
1.61-1.690.23351290.21322528X-RAY DIFFRACTION99.96
1.69-1.80.24371430.20122524X-RAY DIFFRACTION100
1.8-1.940.25761480.19842515X-RAY DIFFRACTION100
1.94-2.130.22771130.17582561X-RAY DIFFRACTION100
2.13-2.440.19661310.16112580X-RAY DIFFRACTION100
2.44-3.080.19781250.18552601X-RAY DIFFRACTION100
3.08-37.010.2121400.1762772X-RAY DIFFRACTION99.97
Refinement TLS params.Method: refined / Origin x: -3.78212012334 Å / Origin y: 18.345556782 Å / Origin z: -6.14215689752 Å
111213212223313233
T0.196476397922 Å2-0.0223614415968 Å20.0275090479701 Å2-0.189527107918 Å2-0.00392502959542 Å2--0.185518874994 Å2
L1.44397241778 °21.38482136838 °20.323127819413 °2-2.15450104342 °20.456918363014 °2--0.612396337007 °2
S-0.156731896131 Å °0.0713456326739 Å °-0.106907260128 Å °-0.157567772939 Å °0.117425494773 Å °-0.149617695103 Å °0.0398368339432 Å °0.0698109207313 Å °-0.0113799799875 Å °
Refinement TLS groupSelection details: (chain 'A' and resid 10 through 178)

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