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- PDB-7uc7: Stat5a Core in complex with Compound 17 -

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Basic information

Entry
Database: PDB / ID: 7uc7
TitleStat5a Core in complex with Compound 17
ComponentsSignal transducer and activator of transcription 5A
KeywordsTRANSCRIPTION/INHIBITOR / STAT5a / ACTIVATOR / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR COMPLEX
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-MQX / Signal transducer and activator of transcription 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.102 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: J.Med.Chem. / Year: 2023
Title: Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia.
Authors: Kaneshige, A. / Bai, L. / Wang, M. / McEachern, D. / Meagher, J.L. / Xu, R. / Kirchhoff, P.D. / Wen, B. / Sun, D. / Stuckey, J.A. / Wang, S.
History
DepositionMar 16, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2023Group: 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 1.2Apr 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)66,6543
Polymers65,8291
Non-polymers8252
Water1,31573
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)238.895, 238.895, 113.304
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-MQX / N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N~3~-(1-benzofuran-5-yl)-N,N-dimethyl-beta-alaninamide


Mass: 732.731 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H39F2N4O8PS / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 73 / 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: 4.73 Å3/Da / Density % sol: 73.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 1.1M Ammonium Tartrate dibasic pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Mar 24, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 22460 / % possible obs: 99.9 % / Redundancy: 11.4 % / Biso Wilson estimate: 59.4 Å2 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.024 / Rrim(I) all: 0.079 / Χ2: 0.947 / Net I/σ(I): 7 / Num. measured all: 256562
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.1-3.1511.61.51511010.9140.4661.5860.87100
3.15-3.2111.61.07810970.9640.3321.1280.882100
3.21-3.2711.50.85211430.9790.2630.8920.88100
3.27-3.3411.50.63511090.9870.1960.6650.905100
3.34-3.4111.50.59311140.9840.1820.620.916100
3.41-3.4911.60.45811130.9880.1410.4790.925100
3.49-3.5811.50.34811110.9920.1070.3640.907100
3.58-3.6811.60.29411210.9950.0910.3070.937100
3.68-3.7811.50.2211190.9970.0680.230.941100
3.78-3.9111.50.19511190.9950.060.2041100
3.91-4.0411.50.1611140.9960.0490.1681.018100
4.04-4.2111.50.12211220.9980.0380.1281.092100
4.21-4.411.50.09811250.9980.030.1031.09100
4.4-4.6311.40.07611230.9980.0240.081.079100
4.63-4.9211.50.06111250.9990.0190.0641.085100
4.92-5.311.40.05411290.9990.0170.0561.015100
5.3-5.8311.40.05111260.9990.0160.0530.902100
5.83-6.6711.30.04211330.9990.0130.0440.808100
6.67-8.411.20.03311480.9990.010.0350.757100
8.4-5010.30.03511680.9970.0120.0370.93398.8

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (3-FEB-2022)refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: previously solved structure in lab

Resolution: 3.102→45.88 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.87 / SU R Cruickshank DPI: 2.836 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.747 / SU Rfree Blow DPI: 0.447 / SU Rfree Cruickshank DPI: 0.461
RfactorNum. reflection% reflectionSelection details
Rfree0.2814 883 4.77 %RANDOM
Rwork0.2219 ---
obs0.2248 18512 82.4 %-
Displacement parametersBiso max: 112.19 Å2 / Biso mean: 61.35 Å2 / Biso min: 6.03 Å2
Baniso -1Baniso -2Baniso -3
1--1.2484 Å20 Å20 Å2
2---1.2484 Å20 Å2
3---2.4969 Å2
Refine analyzeLuzzati coordinate error obs: 0.44 Å
Refinement stepCycle: final / Resolution: 3.102→45.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4407 0 56 73 4536
Biso mean--86.36 32.31 -
Num. residues----557
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1587SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes813HARMONIC5
X-RAY DIFFRACTIONt_it4583HARMONIC10
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_contact3861SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4583HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg6246HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion21.09
LS refinement shellResolution: 3.102→3.18 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3628 19 4.51 %
Rwork0.3004 402 -
obs--27.02 %

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