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- PDB-1pw6: Low Micromolar Small Molecule Inhibitor of IL-2 -

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Basic information

Entry
Database: PDB / ID: 1pw6
TitleLow Micromolar Small Molecule Inhibitor of IL-2
ComponentsInterleukin-2Interleukin 2
KeywordsIMMUNE SYSTEM / IL-2 interleukin 2 small molecule inhibitor
Function / homology
Function and homology information


kappa-type opioid receptor binding / regulation of CD4-positive, alpha-beta T cell proliferation / regulation of T cell homeostatic proliferation / interleukin-2 receptor binding / positive regulation of plasma cell differentiation / response to tacrolimus / glycosphingolipid binding / negative regulation of lymphocyte proliferation / positive regulation of tissue remodeling / negative regulation of T-helper 17 cell differentiation ...kappa-type opioid receptor binding / regulation of CD4-positive, alpha-beta T cell proliferation / regulation of T cell homeostatic proliferation / interleukin-2 receptor binding / positive regulation of plasma cell differentiation / response to tacrolimus / glycosphingolipid binding / negative regulation of lymphocyte proliferation / positive regulation of tissue remodeling / negative regulation of T-helper 17 cell differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / positive regulation of isotype switching to IgG isotypes / leukocyte activation involved in immune response / interleukin-2-mediated signaling pathway / natural killer cell activation / activated T cell proliferation / positive regulation of regulatory T cell differentiation / protein kinase C-activating G protein-coupled receptor signaling pathway / kinase activator activity / negative regulation of B cell apoptotic process / Interleukin-2 signaling / positive regulation of dendritic spine development / positive regulation of activated T cell proliferation / positive regulation of interleukin-17 production / positive regulation of immunoglobulin production / T cell differentiation / Interleukin receptor SHC signaling / positive regulation of B cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of protein phosphorylation / cytokine activity / growth factor activity / negative regulation of inflammatory response / positive regulation of inflammatory response / positive regulation of type II interferon production / cell-cell signaling / positive regulation of cytosolic calcium ion concentration / RAF/MAP kinase cascade / positive regulation of cell growth / carbohydrate binding / response to ethanol / transcription by RNA polymerase II / adaptive immune response / cell adhesion / immune response / positive regulation of cell population proliferation / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region
Similarity search - Function
Interleukin-2 / Interleukin-2, conserved site / Interleukin 2 / Interleukin-2 signature. / Interleukin-2 family / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-FRB / Interleukin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsThanos, C.D. / Randal, M. / Wells, J.A.
CitationJournal: J.Am.Chem.Soc. / Year: 2003
Title: Potent small-molecule binding to a dynamic hot spot on IL-2.
Authors: Thanos, C.D. / Randal, M. / Wells, J.A.
History
DepositionJun 30, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software
Revision 1.4Feb 14, 2018Group: Experimental preparation / Category: exptl_crystal_grow
Item: _exptl_crystal_grow.pdbx_details / _exptl_crystal_grow.temp

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Interleukin-2
B: Interleukin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0375
Polymers30,8722
Non-polymers1,1653
Water0
1
A: Interleukin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,0673
Polymers15,4361
Non-polymers6312
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Interleukin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,9702
Polymers15,4361
Non-polymers5341
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Interleukin-2
hetero molecules

A: Interleukin-2
hetero molecules

B: Interleukin-2
hetero molecules

B: Interleukin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,07410
Polymers61,7444
Non-polymers2,3306
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/41
crystal symmetry operation3_645-y+1,x-1,z+1/41
crystal symmetry operation5_755-x+2,y,-z1
Buried area8360 Å2
ΔGint-106 kcal/mol
Surface area25200 Å2
MethodPISA
4
A: Interleukin-2
hetero molecules

B: Interleukin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0375
Polymers30,8722
Non-polymers1,1653
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_755-x+2,y,-z1
Buried area3000 Å2
ΔGint-45 kcal/mol
Surface area13780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.889, 79.889, 171.891
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122

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Components

#1: Protein Interleukin-2 / Interleukin 2 / IL-2 / T-cell growth factor / TCGF / Aldesleukin


Mass: 15435.979 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL2 / Plasmid: prset / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL-21 / References: UniProt: P60568
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-FRB / 2-CYCLOHEXYL-N-(2-{4-[5-(2,3-DICHLORO-PHENYL)-2H-PYRAZOL-3-YL]-PIPERIDIN-1-YL}-2-OXO-ETHYL)-2-GUANIDINO-ACETAMIDE / SP2456


Mass: 534.481 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H33Cl2N7O2

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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: 4.44 Å3/Da / Density % sol: 72.3 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 5.9
Details: lithium sulfate, ammonium sulfate, pH 5.9, VAPOR DIFFUSION, HANGING DROP
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
10.5 MAmSulf1reservoir
275 mMlithium sulfate1reservoir
30.1 Msodium citrate1reservoirpH5.9

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Sep 9, 2001
RadiationMonochromator: Yale Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. all: 17846 / Num. obs: 17310 / % possible obs: 97 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.6→2.69 Å / % possible all: 97.9
Reflection
*PLUS
Highest resolution: 2.6 Å / Lowest resolution: 10 Å / Num. obs: 16176 / % possible obs: 97 % / Rmerge(I) obs: 0.143
Reflection shell
*PLUS
% possible obs: 97.9 % / Rmerge(I) obs: 0.374 / Mean I/σ(I) obs: 4.3

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Processing

Software
NameVersionClassification
REFMAC5.1.19refinement
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→10 Å / Cor.coef. Fo:Fc: 0.859 / Cor.coef. Fo:Fc free: 0.824 / SU B: 14.087 / SU ML: 0.273 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.359 / ESU R Free: 0.282 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.29216 857 5 %RANDOM
Rwork0.25753 ---
all0.25924 16704 --
obs0.25924 16176 97.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 25.151 Å2
Baniso -1Baniso -2Baniso -3
1-0.16 Å20 Å20 Å2
2--0.16 Å20 Å2
3----0.31 Å2
Refinement stepCycle: LAST / Resolution: 2.6→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2032 0 77 0 2109
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222147
X-RAY DIFFRACTIONr_angle_refined_deg1.2382.0232904
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.1525247
X-RAY DIFFRACTIONr_chiral_restr0.0540.2344
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.021525
X-RAY DIFFRACTIONr_nbd_refined0.1770.2889
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0940.237
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1440.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0520.23
X-RAY DIFFRACTIONr_mcbond_it1.8762.51250
X-RAY DIFFRACTIONr_mcangle_it3.40552041
X-RAY DIFFRACTIONr_scbond_it1.662.5897
X-RAY DIFFRACTIONr_scangle_it2.8045863
LS refinement shellResolution: 2.6→2.685 Å / Total num. of bins used: 15 /
RfactorNum. reflection
Rfree0.362 89
Rwork0.356 1466
Refinement TLS params.

Method: refined / 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)
12.2744-0.93870.01671.0291.30274.49030.0208-0.13090.1115-0.12090.0940.0474-0.24720.3094-0.11480.0188-0.03160.02270.0801-0.01380.049776.72530.997619.783
23.2089-0.79910.61740.8928-0.30170.51290.0275-0.157-0.0421-0.06740.0858-0.00160.0555-0.0059-0.11330.01960.0087-0.00360.0930.00590.0733100.919814.7794-0.3297
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA6 - 1326 - 132
3X-RAY DIFFRACTION2BB5 - 1335 - 133
Refinement
*PLUS
Lowest resolution: 10 Å / Rfactor Rfree: 0.292 / Rfactor Rwork: 0.257
Solvent computation
*PLUS
Displacement parameters
*PLUS

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