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- PDB-9big: Stat6 bound to degrader AK-1690 -

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Basic information

Entry
Database: PDB / ID: 9big
TitleStat6 bound to degrader AK-1690
ComponentsSignal transducer and activator of transcription 6
KeywordsTRANSCRIPTION / inhibitor complex
Function / homology
Function and homology information


regulation of mast cell proliferation / mammary gland morphogenesis / positive regulation of isotype switching to IgE isotypes / negative regulation of type 2 immune response / T-helper 1 cell lineage commitment / STAT6-mediated induction of chemokines / interleukin-4-mediated signaling pathway / isotype switching to IgE isotypes / mammary gland epithelial cell proliferation / growth hormone receptor signaling pathway via JAK-STAT ...regulation of mast cell proliferation / mammary gland morphogenesis / positive regulation of isotype switching to IgE isotypes / negative regulation of type 2 immune response / T-helper 1 cell lineage commitment / STAT6-mediated induction of chemokines / interleukin-4-mediated signaling pathway / isotype switching to IgE isotypes / mammary gland epithelial cell proliferation / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / Downstream signal transduction / RNA polymerase II transcription regulatory region sequence-specific DNA binding / defense response / response to peptide hormone / RNA polymerase II transcription regulator complex / transcription coactivator binding / cytokine-mediated signaling pathway / regulation of cell population proliferation / positive regulation of cold-induced thermogenesis / DNA-binding transcription activator activity, RNA polymerase II-specific / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / regulation of transcription by RNA polymerase II / chromatin / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
STAT6, C-terminal / STAT6, SH2 domain / STAT6 C-terminal / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain ...STAT6, C-terminal / STAT6, SH2 domain / STAT6 C-terminal / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain / STAT protein, protein interaction domain / Signal transducer and activator of transcription, linker domain / STAT protein, protein interaction domain / STAT transcription factor, N-terminal domain superfamily / Transcription factor STAT / STAT transcription factor, coiled coil / p53-like transcription factor, DNA-binding / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily
Similarity search - Domain/homology
: / Signal transducer and activator of transcription 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.304 Å
AuthorsMallik, L. / Stuckey, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA046592 United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader.
Authors: Kaneshige, A. / Yang, Y. / Bai, L. / Wang, M. / Xu, R. / Mallik, L. / Chinnaswamy, K. / Metwally, H. / Wang, Y. / McEachern, D. / Tosovic, J. / Yang, C.Y. / Kirchhoff, P.D. / Meagher, J.L. / ...Authors: Kaneshige, A. / Yang, Y. / Bai, L. / Wang, M. / Xu, R. / Mallik, L. / Chinnaswamy, K. / Metwally, H. / Wang, Y. / McEachern, D. / Tosovic, J. / Yang, C.Y. / Kirchhoff, P.D. / Meagher, J.L. / Stuckey, J.A. / Wang, S.
History
DepositionApr 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Signal transducer and activator of transcription 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2412
Polymers61,2251
Non-polymers1,0161
Water2,108117
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.505, 103.505, 53.059
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

#1: Protein Signal transducer and activator of transcription 6 / IL-4 Stat


Mass: 61225.355 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STAT6 / Production host: Escherichia coli (E. coli) / References: UniProt: P42226
#2: Chemical ChemComp-A1AQQ / [(2-{[(2S)-1-{(2S,4S)-4-[(7-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}hept-6-yn-1-yl)oxy]-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-1-benzothiophen-5-yl)di(fluoro)methyl]phosphonic acid


Mass: 1016.053 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H56F2N5O11PS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.68 Å3/Da / Density % sol: 54.11 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 0.1 M succinic acid pH 7.0, 15% (w/v) PEG 3350, 6 mM strontium chloride hexahydrate, and 10% mixed additive (0.33% w/v 1,5-Naphthalenedisulfonic acid disodium salt, 0.33% w/v Naphthalene- ...Details: 0.1 M succinic acid pH 7.0, 15% (w/v) PEG 3350, 6 mM strontium chloride hexahydrate, and 10% mixed additive (0.33% w/v 1,5-Naphthalenedisulfonic acid disodium salt, 0.33% w/v Naphthalene-1,3,6-trisulfonic acid trisodium salt hydrate, 0.33% w/v PIPES, and 0.02 M HEPES sodium pH 6.8)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.127 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 3.22→50 Å / Num. obs: 10231 / % possible obs: 99.6 % / Redundancy: 10.5 % / CC1/2: 0.995 / CC star: 0.999 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.024 / Rrim(I) all: 0.08 / Χ2: 0.921 / Net I/σ(I): 7.5 / Num. measured all: 106933
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
3.22-3.289.21.0284970.7840.9380.3531.0870.76100
3.28-3.349.80.9175260.830.9520.3040.9670.74499.6
3.34-3.410.40.8944780.8160.9480.2910.9410.879100
3.4-3.4710.70.6615320.8970.9730.2110.6940.862100
3.47-3.5410.60.5265140.9460.9860.1670.5520.88299.8
3.54-3.6310.90.445110.9450.9860.1390.4610.896100
3.63-3.7210.70.345190.9650.9910.1080.3570.94100
3.72-3.8210.50.2745190.980.9950.0870.2880.96599.8
3.82-3.9310.60.2114910.9820.9950.0680.2220.98100
3.93-4.069.90.1675290.990.9980.0550.1760.951100
4.06-4.29.10.1214880.990.9980.0420.1291.01797.2
4.2-4.3710.20.1065140.9950.9990.0340.1110.95799.2
4.37-4.5711.20.0915040.9960.9990.0280.0951.004100
4.57-4.8111.20.0775380.9980.9990.0240.081.022100
4.81-5.1111.30.075060.9980.9990.0220.0730.991100
5.11-5.511.10.0675170.99810.0210.070.956100
5.5-6.06110.0655220.9980.9990.020.0680.99100
6.06-6.9310.50.0565100.99810.0180.0590.932100
6.93-8.739.20.045040.99910.0130.0420.78197.5
8.73-50110.0375120.99910.0120.0390.85299.6

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (8-JUN-2022)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.304→33.88 Å / Cor.coef. Fo:Fc: 0.899 / Cor.coef. Fo:Fc free: 0.806 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.577
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2887 492 5.45 %RANDOM
Rwork0.2046 ---
obs0.2092 9026 94.7 %-
Displacement parametersBiso mean: 51.37 Å2
Baniso -1Baniso -2Baniso -3
1--0.2233 Å20 Å20 Å2
2---0.2233 Å20 Å2
3---0.4467 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 3.304→33.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3227 0 71 117 3415
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0063432HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.94706HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1216SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes620HARMONIC5
X-RAY DIFFRACTIONt_it3376HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.41
X-RAY DIFFRACTIONt_other_torsion19.9
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion429SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2723SEMIHARMONIC4
LS refinement shellResolution: 3.304→3.4 Å
RfactorNum. reflection% reflection
Rfree0.4002 -7.96 %
Rwork0.2436 347 -
obs--49.67 %

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