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- PDB-9fl3: Crystal structure of IL-17A in complex with compound 26 -

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Basic information

Entry
Database: PDB / ID: 9fl3
TitleCrystal structure of IL-17A in complex with compound 26
ComponentsInterleukin-17A
KeywordsCYTOKINE / Inhibitor / Complex
Function / homology
Function and homology information


positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / cell death / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / negative regulation of inflammatory response to wounding / positive regulation of chemokine (C-X-C motif) ligand 1 production / interleukin-17-mediated signaling pathway ...positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / cell death / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / negative regulation of inflammatory response to wounding / positive regulation of chemokine (C-X-C motif) ligand 1 production / interleukin-17-mediated signaling pathway / intestinal epithelial structure maintenance / fibroblast activation / positive regulation of bicellular tight junction assembly / 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 / positive regulation of interleukin-6 production / response to wounding / positive regulation of tumor necrosis factor production / cell-cell signaling / defense response to Gram-negative bacterium / Interleukin-4 and Interleukin-13 signaling / gene expression / adaptive immune response / defense response to Gram-positive bacterium / immune response / inflammatory 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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.068 Å
AuthorsRondeau, J.M. / Lehmann, S. / Scheufler, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and alpha-Fluoroacrylate Containing IL-17 Inhibitors.
Authors: Velcicky, J. / Bauer, M.R. / Schlapbach, A. / Lapointe, G. / Meyer, A. / Vogtle, M. / Blum, E. / Ngo, E. / Rolando, C. / Nimsgern, P. / Teixeira-Fouchard, S. / Lehmann, H. / Furet, P. / ...Authors: Velcicky, J. / Bauer, M.R. / Schlapbach, A. / Lapointe, G. / Meyer, A. / Vogtle, M. / Blum, E. / Ngo, E. / Rolando, C. / Nimsgern, P. / Teixeira-Fouchard, S. / Lehmann, H. / Furet, P. / Berst, F. / Schumann, J. / Stringer, R. / Larger, P. / Schmid, C. / Prendergast, C.T. / Riek, S. / Schmutz, P. / Lehmann, S. / Berghausen, J. / Scheufler, C. / Rondeau, J.M. / Burkhart, C. / Knoepfel, T. / Gommermann, N.
History
DepositionJun 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)29,0913
Polymers28,5022
Non-polymers5891
Water95553
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5680 Å2
ΔGint-25 kcal/mol
Surface area10870 Å2
Unit cell
Length a, b, c (Å)64.456, 84.581, 119.286
Angle α, β, γ (deg.)90, 90, 90
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: 14251.060 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-A1IDS / (~{E})-~{N}-[(~{S})-[4,4-bis(fluoranyl)cyclohexyl]-[7-[(1~{S})-2-methoxy-1-[(4~{S})-2-oxidanylidene-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-3-cyclopropyl-2-fluoranyl-prop-2-enamide


Mass: 588.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30F6N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.85 Å3/Da / Density % sol: 56.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1M citrate pH 5.5 10% PEG 10,000 12% isopropanol 10% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99988 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 2.068→59.643 Å / Num. obs: 20290 / % possible obs: 100 % / Redundancy: 10 % / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.023 / Rrim(I) all: 0.072 / Net I/σ(I): 13.5
Reflection shellResolution: 2.068→2.104 Å / Redundancy: 10 % / Rmerge(I) obs: 3.593 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 991 / CC1/2: 0.365 / Rpim(I) all: 1.193 / Rrim(I) all: 3.769 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.068→59.64 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.942 / SU R Cruickshank DPI: 0.166 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.166 / SU Rfree Blow DPI: 0.149 / SU Rfree Cruickshank DPI: 0.15
RfactorNum. reflection% reflectionSelection details
Rfree0.2524 1018 -RANDOM
Rwork0.2287 ---
obs0.2299 20169 99.3 %-
Displacement parametersBiso mean: 70.94 Å2
Baniso -1Baniso -2Baniso -3
1-6.8136 Å20 Å20 Å2
2---8.5821 Å20 Å2
3---1.7685 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.068→59.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1575 0 41 53 1669
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081665HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.992279HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d558SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes279HARMONIC5
X-RAY DIFFRACTIONt_it1665HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion213SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1145SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.74
X-RAY DIFFRACTIONt_other_torsion12.68
LS refinement shellResolution: 2.07→2.09 Å
RfactorNum. reflection% reflection
Rfree0.3243 21 -
Rwork0.407 --
obs0.4022 404 80.59 %
Refinement TLS params.

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)Origin x (Å)Origin y (Å)Origin z (Å)
15.7032-0.6836-5.02210.77790.80445.15340.2729-0.1353-0.2007-0.1353-0.0848-0.1799-0.2007-0.1799-0.1881-0.065-0.01480.016-0.00940.0361-0.0116-20.4031-7.988-11.5115
26.46410.0304-5.70120.35830.28755.3916-0.4524-0.04940.5907-0.0494-0.0214-0.15290.5907-0.15290.4738-0.0252-0.01980.0547-0.0310.0284-0.006-20.4666-20.2452-11.1571
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A42 - 150
2X-RAY DIFFRACTION1{ A|* }A201
3X-RAY DIFFRACTION2{ B|* }B42 - 150

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