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- PDB-8uss: IL17A complexed to Compound 7 -

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Basic information

Entry
Database: PDB / ID: 8uss
TitleIL17A complexed to Compound 7
ComponentsInterleukin-17A
KeywordsCYTOKINE / Homodimer / inhibitor / DEL
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 / MOLECULAR REPLACEMENT / Resolution: 1.47 Å
AuthorsArgiriadi, M.A. / Ramos, A.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.
Authors: Ramos, A.L. / Goedken, E.R. / Frank, K.E. / Argiriadi, M.A. / Bazzaz, S. / Bian, Z. / Brown, J.T.C. / Centrella, P.A. / Chen, H.J. / Disch, J.S. / Donner, P.L. / Duignan, D.B. / Gikunju, D. ...Authors: Ramos, A.L. / Goedken, E.R. / Frank, K.E. / Argiriadi, M.A. / Bazzaz, S. / Bian, Z. / Brown, J.T.C. / Centrella, P.A. / Chen, H.J. / Disch, J.S. / Donner, P.L. / Duignan, D.B. / Gikunju, D. / Greszler, S.N. / Guie, M.A. / Habeshian, S. / Hartl, H.E. / Hein, C.D. / Hutchins, C.W. / Jetson, R. / Keefe, A.D. / Khan, H. / Li, H.Q. / Olszewski, A. / Ortiz Cardona, B.J. / Osuma, A. / Panchal, S.C. / Phelan, R. / Qiu, W. / Shotwell, J.B. / Shrestha, A. / Srikumaran, M. / Su, Z. / Sun, C. / Upadhyay, A.K. / Wood, M.D. / Wu, H. / Zhang, R. / Zhang, Y. / Zhao, G. / Zhu, H. / Webster, M.P.
History
DepositionOct 29, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2024Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 1, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,0663
Polymers14,5371
Non-polymers5292
Water1,29772
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)36.600, 50.380, 157.360
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-310-

HOH

21A-322-

HOH

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Components

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


Mass: 14537.343 Da / Num. of mol.: 1
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-XCW / 4,5-dichloro-N-[(1S)-1-cyclohexyl-2-{[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]amino}-2-oxoethyl]-1H-pyrrole-2-carboxamide


Mass: 493.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26Cl2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#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.: 72 / 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: 2.48 Å3/Da / Density % sol: 50.46 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / Details: 15% w/v PEG 8K, 0.2 M MgCl2, 0.1 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.465→78.7 Å / Num. obs: 21942 / % possible obs: 85.6 % / Redundancy: 5.1 % / Biso Wilson estimate: 20.53 Å2 / CC1/2: 1 / Rsym value: 0.04 / Net I/σ(I): 21.9
Reflection shellResolution: 1.465→1.526 Å / Num. unique obs: 1098 / CC1/2: 0.88 / Rsym value: 0.269

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
REFMACv7.0refinement
PHASERphasing
autoPROCdata reduction
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.47→15.78 Å / SU ML: 0.1811 / Cross valid method: FREE R-VALUE / σ(F): 0.32 / Phase error: 27.7431
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2355 1053 4.82 %
Rwork0.2214 20777 -
obs0.222 21830 86.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.22 Å2
Refinement stepCycle: LAST / Resolution: 1.47→15.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms844 0 34 72 950
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0227914
X-RAY DIFFRACTIONf_angle_d2.09231254
X-RAY DIFFRACTIONf_chiral_restr0.1503136
X-RAY DIFFRACTIONf_plane_restr0.0148170
X-RAY DIFFRACTIONf_dihedral_angle_d15.2871327
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.47-1.540.3407550.33431230X-RAY DIFFRACTION41.32
1.54-1.620.3017990.26051972X-RAY DIFFRACTION66.66
1.62-1.720.2831200.24522509X-RAY DIFFRACTION84.51
1.72-1.850.28281640.24692871X-RAY DIFFRACTION97.03
1.85-2.040.25091440.23272988X-RAY DIFFRACTION100
2.04-2.330.23191530.22143004X-RAY DIFFRACTION99.91
2.33-2.940.24751590.22113038X-RAY DIFFRACTION99.88
2.94-15.780.21071590.2083165X-RAY DIFFRACTION99.67

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