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- PDB-7tva: Stat5a Core in complex with AK2292 -

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Basic information

Entry
Database: PDB / ID: 7tva
TitleStat5a Core in complex with AK2292
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-KOO / MALONATE ION / DI(HYDROXYETHYL)ETHER / Signal transducer and activator of transcription 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.835 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
B: Signal transducer and activator of transcription 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,1127
Polymers131,6572
Non-polymers2,4555
Water4,179232
1
A: Signal transducer and activator of transcription 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,0053
Polymers65,8291
Non-polymers1,1762
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Signal transducer and activator of transcription 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,1074
Polymers65,8291
Non-polymers1,2783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)232.476, 232.476, 112.473
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 65828.734 Da / Num. of mol.: 2
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-KOO / N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N-(5-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}pent-4-yn-1-yl)-N-methyl-N~3~-[4-(1,3-thiazol-2-yl)phenyl]-beta-alaninamide / AK2292


Mass: 1070.127 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C52H54F2N7O10PS2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-MLI / MALONATE ION / Malonic acid


Mass: 102.046 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H2O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 4.44 Å3/Da / Density % sol: 72.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.0M Na Malonate, 20% peg 400, 1% Jeffamine

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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: Nov 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1271 Å / Relative weight: 1
ReflectionResolution: 2.834→50 Å / Num. obs: 53485 / % possible obs: 99.7 % / Redundancy: 5.1 % / Biso Wilson estimate: 65.75 Å2 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.037 / Rrim(I) all: 0.085 / Χ2: 0.83 / Net I/σ(I): 9.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.85-2.95.11.24626690.5030.6121.390.607100
2.9-2.955.11.03826490.6070.511.1580.619100
2.95-3.015.10.85426680.6590.4210.9540.65999.9
3.01-3.0750.70227050.7510.350.7860.67499.7
3.07-3.144.80.55326670.8180.280.6210.69599.7
3.14-3.214.40.40626920.8610.2140.4610.74398.7
3.21-3.294.50.31826100.9010.1680.3610.75298.4
3.29-3.385.40.2626460.9450.1240.2880.839100
3.38-3.485.50.20927080.9610.0990.2310.939100
3.48-3.595.50.16127140.9740.0760.1791.029100
3.59-3.725.50.13226370.9790.0630.1461.054100
3.72-3.875.40.11227250.9840.0540.1241.134100
3.87-4.045.30.09526710.9850.0460.1051.097100
4.04-4.265.20.08126850.9860.0390.091.077100
4.26-4.525.20.0726810.9890.0340.0781100
4.52-4.875.10.06526760.9920.0320.0730.97100
4.87-5.364.90.0626830.9910.030.0670.85699.9
5.36-6.144.60.05526670.9880.0280.0620.68599.3
6.14-7.735.20.04726640.9940.0220.0520.56599.2
7.73-505.50.04226680.9960.020.0470.47699.4

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Phasing

PhasingMethod: molecular replacement

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Processing

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

Resolution: 2.835→37.51 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.894 / SU R Cruickshank DPI: 0.494 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.449 / SU Rfree Blow DPI: 0.295 / SU Rfree Cruickshank DPI: 0.307
RfactorNum. reflection% reflectionSelection details
Rfree0.2463 2498 5.02 %RANDOM
Rwork0.2025 ---
obs0.2047 49797 92.6 %-
Displacement parametersBiso max: 122.63 Å2 / Biso mean: 56.68 Å2 / Biso min: 20.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.7551 Å20 Å20 Å2
2---0.7551 Å20 Å2
3---1.5102 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: final / Resolution: 2.835→37.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8768 0 169 232 9169
Biso mean--61.04 45.24 -
Num. residues----1112
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3185SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1654HARMONIC5
X-RAY DIFFRACTIONt_it9175HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1194SEMIHARMONIC5
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_contact6919SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9175HARMONIC20.006
X-RAY DIFFRACTIONt_angle_deg12502HARMONIC20.86
X-RAY DIFFRACTIONt_omega_torsion2.55
X-RAY DIFFRACTIONt_other_torsion19.7
LS refinement shellResolution: 2.835→2.89 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3066 38 3.82 %
Rwork0.2684 958 -
obs--31.56 %
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)
14.8981-2.16921.08042.002-0.407700.11160.20580.04730.135-0.15510.1028-0.05380.09130.04350.08840.3419-0.03340.10470.0423-0.123613.994435.064830.5321
21.4858-1.011-0.0522.8454-0.52771.5139-0.0578-0.1056-0.17430.3789-0.0491-0.2469-0.3005-0.05060.1069-0.06620.041-0.2115-0.01840.16280.051148.08472.350350.442
35.6311-2.19351.35732.052-0.34570-0.22350.1023-0.0584-0.12880.1892-0.1238-0.13370.09370.0342-0.1530.11120.00390.35180.0093-0.189220.422631.22335.2974
44.05960.2050.35811.15680.51371.7424-0.17910.58620.1209-0.34020.10610.3195-0.38790.10460.0730.12110.1276-0.3307-0.11420.1146-0.0185-26.299939.6453-14.4533
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|138 - A|443 }A138 - 443
2X-RAY DIFFRACTION2{ A|444 - A|699 }A444 - 699
3X-RAY DIFFRACTION3{ B|138 - B|443 }B138 - 443
4X-RAY DIFFRACTION4{ B|444 - B|699 }B444 - 699

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