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- PDB-8usr: IL17A homodimer complexed to Compound 23 -

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Basic information

Entry
Database: PDB / ID: 8usr
TitleIL17A homodimer complexed to Compound 23
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 / 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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 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

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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
C: Interleukin-17A
D: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,0918
Polymers58,1494
Non-polymers1,9414
Water3,891216
1
A: Interleukin-17A
B: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,0454
Polymers29,0752
Non-polymers9712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4730 Å2
ΔGint-26 kcal/mol
Surface area10370 Å2
MethodPISA
2
C: Interleukin-17A

D: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,0454
Polymers29,0752
Non-polymers9712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_554-x,y,-z-1/21
Buried area4600 Å2
ΔGint-26 kcal/mol
Surface area10250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.110, 159.090, 107.180
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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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.: 4
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-XCE / ~{N}-[(2~{S})-1-[[(1~{S})-1-(8~{a}~{H}-imidazo[1,2-a]pyrimidin-2-yl)ethyl]amino]-1-oxidanylidene-4-phenyl-butan-2-yl]-4,5-bis(chloranyl)-1~{H}-pyrrole-2-carboxamide


Mass: 485.366 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H22Cl2N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 216 / Source method: isolated from a natural source / Formula: H2O
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: 2.28 Å3/Da / Density % sol: 45.97 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 2 M NaCl, 0.1 M NaH2PO4, 0.1 M KH2PO4, 0.1 M MES pH 6.5

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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: Jan 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.83→79.5 Å / Num. obs: 45560 / % possible obs: 80.7 % / Redundancy: 5.7 % / Biso Wilson estimate: 34.05 Å2 / CC1/2: 1 / Rsym value: 0.12 / Net I/σ(I): 7.4
Reflection shellResolution: 1.831→1.963 Å / Num. unique obs: 1901 / CC1/2: 0.579 / Rsym value: 1.193

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
BUSTERrefinement
REFMACv7.0refinement
autoPROCdata reduction
PHASERphasing
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→32.59 Å / SU ML: 0.2245 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 31.7688
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2503 1949 5.13 %
Rwork0.2202 36059 -
obs0.2217 38008 80.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.58 Å2
Refinement stepCycle: LAST / Resolution: 1.83→32.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3052 0 132 216 3400
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073282
X-RAY DIFFRACTIONf_angle_d1.13324490
X-RAY DIFFRACTIONf_chiral_restr0.0663483
X-RAY DIFFRACTIONf_plane_restr0.0066622
X-RAY DIFFRACTIONf_dihedral_angle_d5.4504459
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.83-1.870.4836130.3984247X-RAY DIFFRACTION8.18
1.88-1.930.5395170.3839432X-RAY DIFFRACTION16.28
1.93-1.980.3583950.32641854X-RAY DIFFRACTION58.27
1.98-2.050.37781620.31882691X-RAY DIFFRACTION85.52
2.05-2.120.38081470.3082545X-RAY DIFFRACTION80.62
2.12-2.20.32321660.27943112X-RAY DIFFRACTION97.79
2.2-2.30.2781410.26142808X-RAY DIFFRACTION87.98
2.3-2.430.30391770.24943153X-RAY DIFFRACTION99.31
2.43-2.580.28441860.24173155X-RAY DIFFRACTION99.11
2.58-2.780.27181680.22962985X-RAY DIFFRACTION93.64
2.78-3.060.2471830.2163187X-RAY DIFFRACTION99.21
3.06-3.50.26331530.20193232X-RAY DIFFRACTION99.62
3.5-4.40.19191610.1813272X-RAY DIFFRACTION99.8
4.41-32.590.21111800.20883386X-RAY DIFFRACTION99.89

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