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- PDB-8dpw: The structure of Interleukin-11 Mutein -

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Basic information

Entry
Database: PDB / ID: 8dpw
TitleThe structure of Interleukin-11 Mutein
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-serine 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-serine phosphorylation / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of MAPK cascade / cell population proliferation / 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: 1.8 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)18,3962
Polymers18,3001
Non-polymers961
Water1,27971
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)27.230, 37.097, 68.532
Angle α, β, γ (deg.)90.000, 101.306, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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


Mass: 18300.293 Da / Num. of mol.: 1 / Mutation: A58P, M59A, S60I, A61D, G62Y, 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 1.85 Å3/Da / Density % sol: 33.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 27% PEG 3350, 0.1 M bis-tris propane pH 9, 0.2 M ammonium sulfate, 5 mM praseodymium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.8→37.101 Å / Num. obs: 12637 / % possible obs: 100 % / Redundancy: 6.8 % / Biso Wilson estimate: 32.06 Å2 / CC1/2: 0.99 / Rpim(I) all: 0.043 / Rrim(I) all: 0.083 / Rsym value: 0.07 / Net I/σ(I): 11.8
Reflection shellResolution: 1.8→1.84 Å / Redundancy: 6.9 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 761 / CC1/2: 0.603 / Rpim(I) all: 0.719 / Rrim(I) all: 1.374 / Rsym value: 1.167 / % possible all: 100

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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: 1.8→33.6 Å / SU ML: 0.2633 / Cross valid method: FREE R-VALUE / σ(F): 1.41 / Phase error: 28.7198
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2271 590 4.67 %
Rwork0.195 12033 -
obs0.1966 12623 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.65 Å2
Refinement stepCycle: LAST / Resolution: 1.8→33.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1290 0 5 71 1366
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00281321
X-RAY DIFFRACTIONf_angle_d0.63041805
X-RAY DIFFRACTIONf_chiral_restr0.0307214
X-RAY DIFFRACTIONf_plane_restr0.0039235
X-RAY DIFFRACTIONf_dihedral_angle_d20.2876507
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.980.30191350.27082982X-RAY DIFFRACTION99.94
1.98-2.270.25941500.21012994X-RAY DIFFRACTION100
2.27-2.860.22871440.2042993X-RAY DIFFRACTION99.97
2.86-33.60.21271610.17963064X-RAY DIFFRACTION99.88
Refinement TLS params.Method: refined / Origin x: -6.7465929837 Å / Origin y: 7.63166353347 Å / Origin z: -17.8512695497 Å
111213212223313233
T0.206105356824 Å2-0.00290783454012 Å2-0.00569778296405 Å2-0.249400734579 Å20.00966137756472 Å2--0.258882709241 Å2
L0.366938587851 °2-0.0493751570986 °20.268698420724 °2-0.549501056177 °20.643904151039 °2--2.54326388391 °2
S0.0383218017539 Å °0.114727490202 Å °0.068232514095 Å °0.0204408491041 Å °-0.0892693935799 Å °0.0928335761868 Å °-0.0570006552388 Å °0.0332663383181 Å °-1.57960656854E-5 Å °
Refinement TLS groupSelection details: (chain 'A' and resid 31 through 178)

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