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- PDB-7tvb: Stat5A Core in Complex with AK305 -

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Basic information

Entry
Database: PDB / ID: 7tvb
TitleStat5A Core in Complex with AK305
ComponentsSignal transducer and activator of transcription 5A
KeywordsTRANSCRIPTION / Stat5a / Activator
Function / homology
Function and homology information


eosinophil differentiation / taurine metabolic process / reelin-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / STAT5 Activation / Erythropoietin activates STAT5 ...eosinophil differentiation / taurine metabolic process / reelin-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / STAT5 Activation / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / interleukin-15-mediated signaling pathway / Signaling by cytosolic FGFR1 fusion mutants / interleukin-3-mediated signaling pathway / Interleukin-15 signaling / Signaling by Leptin / Interleukin-2 signaling / Interleukin-20 family signaling / STAT5 activation downstream of FLT3 ITD mutants / Prolactin receptor signaling / cell surface receptor signaling pathway via JAK-STAT / regulation of multicellular organism growth / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of blood vessel endothelial cell migration / growth hormone receptor signaling pathway via JAK-STAT / Nuclear signaling by ERBB4 / Nuclear events stimulated by ALK signaling in cancer / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 fusion proteins / lactation / positive regulation of endothelial cell proliferation / Interleukin-7 signaling / Downstream signal transduction / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / defense response / Inactivation of CSF3 (G-CSF) signaling / Signaling by SCF-KIT / response to peptide hormone / cytokine-mediated signaling pathway / RNA polymerase II transcription regulator complex / regulation of cell population proliferation / DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / chromatin / regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytosol
Similarity search - Function
: / STAT5a/5b / : / Signal transducer and activator of transcription, linker domain / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / STAT protein, all-alpha domain / STAT protein, DNA binding domain ...: / STAT5a/5b / : / Signal transducer and activator of transcription, linker domain / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / STAT protein, all-alpha domain / STAT protein, DNA binding domain / STAT protein, protein interaction 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
Chem-KOC / Signal transducer and activator of transcription 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.653 Å
AuthorsMeagher, J.L. / Stuckey, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1-R01-CA244509 United States
CitationJournal: Nat.Chem.Biol. / Year: 2023
Title: A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo.
Authors: Kaneshige, A. / Bai, L. / Wang, M. / McEachern, D. / Meagher, J.L. / Xu, R. / Wang, Y. / Jiang, W. / Metwally, H. / Kirchhoff, P.D. / Zhao, L. / Jiang, H. / Wang, M. / Wen, B. / Sun, D. / ...Authors: Kaneshige, A. / Bai, L. / Wang, M. / McEachern, D. / Meagher, J.L. / Xu, R. / Wang, Y. / Jiang, W. / Metwally, H. / Kirchhoff, P.D. / Zhao, L. / Jiang, H. / Wang, M. / Wen, B. / Sun, D. / Stuckey, J.A. / Wang, S.
History
DepositionFeb 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Signal transducer and activator of transcription 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,7894
Polymers65,8291
Non-polymers9603
Water7,026390
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)239.937, 239.937, 113.224
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32

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Components

#1: Protein Signal transducer and activator of transcription 5A


Mass: 65828.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STAT5A, STAT5 / Production host: Escherichia coli (E. coli) / References: UniProt: P42229
#2: Chemical ChemComp-KOC / N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N,N-dimethyl-N~3~-[4-(1,3-thiazol-2-yl)phenyl]-beta-alaninamide / AK2305


Mass: 775.822 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H40F2N5O7PS2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 390 / 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: 4.76 Å3/Da / Density % sol: 74.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 1M Na Malonate pH 7.0, 1% Jeffamine pH 7.0, 5% peg 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.1271 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1271 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. obs: 36049 / % possible obs: 99.9 % / Redundancy: 20.6 % / Biso Wilson estimate: 57.82 Å2 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.021 / Rrim(I) all: 0.097 / Χ2: 0.997 / Net I/σ(I): 6.3 / Num. measured all: 741459
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.65-2.717.20.97617950.9280.2371.0050.7699.9
2.7-2.7418.90.91717760.9380.2150.9420.795100
2.74-2.820.50.80917830.9450.1830.830.816100
2.8-2.8521.20.70518120.9640.1570.7220.855100
2.85-2.9221.50.5617960.9810.1230.5730.892100
2.92-2.9821.40.48317890.9790.1070.4950.935100
2.98-3.0621.30.42317790.9830.0940.4330.972100
3.06-3.1421.20.35118090.9890.0780.361.02499.9
3.14-3.2320.90.26817830.9930.060.2751.072100
3.23-3.3420.60.22118050.9950.050.2271.12499.8
3.34-3.4619.60.17817730.9950.0410.1831.20699.6
3.46-3.617.60.14117960.9970.0340.1451.28599.5
3.6-3.7621.90.1317980.9970.0280.1331.335100
3.76-3.96220.10918070.9980.0240.1111.32100
3.96-4.2121.90.09418090.9980.0210.0961.281100
4.21-4.5321.70.08117920.9980.0180.0831.199100
4.53-4.9921.50.06718250.9990.0150.0691.02799.9
4.99-5.7120.90.06118150.9990.0140.0620.817100
5.71-7.1918.20.05218320.9990.0120.0530.63299.8
7.19-5021.50.032187510.0070.0330.523100

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.10.4 (20-OCT-2021)refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Previously solved structure in lab

Resolution: 2.653→29.99 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.902 / SU R Cruickshank DPI: 0.325 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.34 / SU Rfree Blow DPI: 0.255 / SU Rfree Cruickshank DPI: 0.253
RfactorNum. reflection% reflectionSelection details
Rfree0.2484 1712 4.98 %RANDOM
Rwork0.2088 ---
obs0.2107 34349 95.3 %-
Displacement parametersBiso max: 101.89 Å2 / Biso mean: 42.69 Å2 / Biso min: 18.16 Å2
Baniso -1Baniso -2Baniso -3
1--0.4831 Å20 Å20 Å2
2---0.4831 Å20 Å2
3---0.9663 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: final / Resolution: 2.653→29.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4446 0 64 390 4900
Biso mean--44.76 45.43 -
Num. residues----558
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1622SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes818HARMONIC5
X-RAY DIFFRACTIONt_it4629HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion599SEMIHARMONIC5
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_contact4046SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4629HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6297HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.06
X-RAY DIFFRACTIONt_other_torsion19.13
LS refinement shellResolution: 2.653→2.68 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3507 39 5.68 %
Rwork0.2779 648 -
obs--55.58 %

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