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- PDB-8cdg: Crystal structure of human IL-17A cytokine in complex with macrocycle -

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Basic information

Entry
Database: PDB / ID: 8cdg
TitleCrystal structure of human IL-17A cytokine in complex with macrocycle
ComponentsInterleukin-17A
KeywordsCYTOKINE / inhibitor / complex / macrocycle
Function / homology
Function and homology information


positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / intestinal epithelial structure maintenance / negative regulation of inflammatory response to wounding / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / cell death / positive regulation of chemokine (C-X-C motif) ligand 1 production ...positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / intestinal epithelial structure maintenance / negative regulation of inflammatory response to wounding / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / cell death / positive regulation of chemokine (C-X-C motif) ligand 1 production / interleukin-17-mediated signaling pathway / positive regulation of bicellular tight junction assembly / fibroblast activation / positive regulation of osteoclast differentiation / positive regulation of cytokine production involved in inflammatory response / keratinocyte proliferation / cellular response to interleukin-1 / defense response to fungus / keratinocyte differentiation / Notch signaling pathway / positive regulation of interleukin-12 production / positive regulation of interleukin-1 beta production / cytokine activity / response to wounding / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / cell-cell signaling / gene expression / Interleukin-4 and Interleukin-13 signaling / defense response to Gram-negative bacterium / adaptive immune response / defense response to Gram-positive bacterium / inflammatory response / immune response / protein heterodimerization activity / external side of plasma membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region
Similarity search - Function
Interleukin-17, chordata / Interleukin-17 family / Interleukin-17 / Cystine-knot cytokine
Similarity search - Domain/homology
Chem-UTF / Interleukin-17A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsSchulze, M.-S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chem Sci / Year: 2023
Title: Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism.
Authors: Shaw, D.J. / Waters, L.C. / Strong, S.L. / Schulze, M.E.D. / Greetham, G.M. / Towrie, M. / Parker, A.W. / Prosser, C.E. / Henry, A.J. / Lawson, A.D.G. / Carr, M.D. / Taylor, R.J. / Hunt, N.T. / Muskett, F.W.
History
DepositionJan 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Interleukin-17A
B: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,4053
Polymers28,6182
Non-polymers7871
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-24 kcal/mol
Surface area11260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.362, 89.771, 116.669
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Interleukin-17A / IL-17 / IL-17A / Cytotoxic T-lymphocyte-associated antigen 8 / CTLA-8


Mass: 14309.096 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL17A, CTLA8, IL17 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16552
#2: Chemical ChemComp-UTF / (9~{S},12~{R},19~{S})-9-[[4-[[(2~{S})-2-cyclohexyl-2-(2-phenylethanoylamino)ethanoyl]amino]phenyl]methyl]-12-methyl-7,10,13,21-tetrakis(oxidanylidene)-8,11,14,20-tetrazaspiro[4.17]docosane-19-carboxylic acid


Mass: 786.956 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C43H58N6O8 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 3.08 Å3/Da / Density % sol: 60.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 100 mM sodium citrate buffer, pH 5.5, 8 % 2-propanol, and 10 % w/v PEG10k

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.9→29.39 Å / Num. obs: 8077 / % possible obs: 99.5 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 22.5
Reflection shellResolution: 2.9→2.98 Å / Num. unique obs: 591 / Rsym value: 0.93

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→29.39 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2569 478 5.93 %
Rwork0.2331 --
obs0.2348 8060 99.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→29.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1532 0 57 0 1589
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0111633
X-RAY DIFFRACTIONf_angle_d1.5352225
X-RAY DIFFRACTIONf_dihedral_angle_d28.835208
X-RAY DIFFRACTIONf_chiral_restr0.082236
X-RAY DIFFRACTIONf_plane_restr0.011294
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.320.33171640.27572477X-RAY DIFFRACTION99
3.32-4.180.29531510.24992509X-RAY DIFFRACTION100
4.19-29.390.22511630.21572596X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -21.6848 Å / Origin y: -14.2437 Å / Origin z: -11.3606 Å
111213212223313233
T0.5066 Å2-0.0385 Å2-0.0893 Å2-0.5972 Å20.1197 Å2--0.4781 Å2
L8.4113 °2-2.5717 °2-6.4705 °2-1.8074 °22.1811 °2--6.0728 °2
S-0.0708 Å °0.1603 Å °-0.3379 Å °-0.1029 Å °0.0369 Å °0.2197 Å °0.1922 Å °-0.1047 Å °0.045 Å °
Refinement TLS groupSelection details: all

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