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- PDB-6tlc: Unphosphorylated human STAT3 in complex with MS3-6 monobody -

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Basic information

Entry
Database: PDB / ID: 6tlc
TitleUnphosphorylated human STAT3 in complex with MS3-6 monobody
Components
  • Monobody
  • Signal transducer and activator of transcription 3
KeywordsTRANSCRIPTION / Inhibitor / Complex / STAT3 / Monobody
Function / homology
Function and homology information


PTK6 Activates STAT3 / RNA sequestering activity / eye photoreceptor cell differentiation / radial glial cell differentiation / negative regulation of primary miRNA processing / retinal rod cell differentiation / leptin-mediated signaling pathway / negative regulation of hydrogen peroxide biosynthetic process / T-helper 17 type immune response / Signalling to STAT3 ...PTK6 Activates STAT3 / RNA sequestering activity / eye photoreceptor cell differentiation / radial glial cell differentiation / negative regulation of primary miRNA processing / retinal rod cell differentiation / leptin-mediated signaling pathway / negative regulation of hydrogen peroxide biosynthetic process / T-helper 17 type immune response / Signalling to STAT3 / negative regulation of neuron migration / POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation / positive regulation of extracellular matrix disassembly / negative regulation of inflammatory response to wounding / primary miRNA binding / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / cellular response to interleukin-17 / T-helper 17 cell lineage commitment / response to leptin / regulation of feeding behavior / sexual reproduction / Interleukin-9 signaling / Interleukin-21 signaling / Transcriptional regulation of pluripotent stem cells / interleukin-9-mediated signaling pathway / MET activates STAT3 / nuclear glucocorticoid receptor binding / interleukin-10-mediated signaling pathway / regulation of cellular response to hypoxia / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / interleukin-2-mediated signaling pathway / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / cellular response to leptin stimulus / interleukin-15-mediated signaling pathway / interleukin-23-mediated signaling pathway / postsynapse to nucleus signaling pathway / Interleukin-23 signaling / negative regulation of stem cell differentiation / astrocyte differentiation / Signaling by cytosolic FGFR1 fusion mutants / STAT3 nuclear events downstream of ALK signaling / Interleukin-15 signaling / Interleukin-37 signaling / Signaling by Leptin / regulation of mitochondrial membrane permeability / positive regulation of cytokine production involved in inflammatory response / Interleukin-27 signaling / Interleukin-35 Signalling / phosphorylation / cell surface receptor signaling pathway via STAT / negative regulation of glycolytic process / positive regulation of vascular endothelial cell proliferation / eating behavior / growth hormone receptor signaling pathway / Signaling by ALK / Interleukin-20 family signaling / Interleukin-6 signaling / temperature homeostasis / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / lncRNA binding / Interleukin-10 signaling / Association of TriC/CCT with target proteins during biosynthesis / positive regulation of ATP biosynthetic process / positive regulation of interleukin-10 production / positive regulation of vascular endothelial growth factor production / somatic stem cell population maintenance / regulation of multicellular organism growth / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / Growth hormone receptor signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / cellular response to hormone stimulus / Nuclear events stimulated by ALK signaling in cancer / intracellular receptor signaling pathway / energy homeostasis / Signaling by CSF3 (G-CSF) / positive regulation of phagocytosis / signaling adaptor activity / negative regulation of canonical NF-kappaB signal transduction / negative regulation of cytokine production involved in inflammatory response / Interleukin-7 signaling / Downstream signal transduction / negative regulation of autophagy / transforming growth factor beta receptor signaling pathway / protein sequestering activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of erythrocyte differentiation / positive regulation of interleukin-1 beta production / response to ischemia / acute-phase response / positive regulation of interleukin-8 production / phosphatidylinositol 3-kinase/protein kinase B signal transduction / mRNA transcription by RNA polymerase II / defense response / Signaling by SCF-KIT / modulation of chemical synaptic transmission / Cytoprotection by HMOX1
Similarity search - Function
STAT3, SH2 domain / STAT transcription factor, DNA-binding domain / STAT transcription factor, all-alpha 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 transcription factor, coiled-coil domain / STAT protein, DNA binding domain ...STAT3, SH2 domain / STAT transcription factor, DNA-binding domain / STAT transcription factor, all-alpha 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 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 / Glutathione S-transferase Yfyf (Class Pi); Chain A, domain 2 / p53-like transcription factor, DNA-binding / SH2 domain / Src homology 2 (SH2) domain profile. / SH2 domain / SH2 domain superfamily / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Signal transducer and activator of transcription 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsLa Sala, G. / Lau, K. / Reynaud, A. / Pojer, F. / Hantschel, O.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
European Research Council (ERC)ERC-2016-CoG 682311-ONCOINTRABODY Switzerland
CitationJournal: Nat Commun / Year: 2020
Title: Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.
Authors: La Sala, G. / Michiels, C. / Kukenshoner, T. / Brandstoetter, T. / Maurer, B. / Koide, A. / Lau, K. / Pojer, F. / Koide, S. / Sexl, V. / Dumoutier, L. / Hantschel, O.
History
DepositionDec 2, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Database references / Category: citation / Item: _citation.title
Revision 1.2Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Signal transducer and activator of transcription 3
A: Signal transducer and activator of transcription 3
D: Monobody
C: Monobody


Theoretical massNumber of molelcules
Total (without water)156,7534
Polymers156,7534
Non-polymers00
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry, Binding with 5nM affinity
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6430 Å2
ΔGint-27 kcal/mol
Surface area57480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.310, 111.310, 483.467
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: Protein Signal transducer and activator of transcription 3 / Acute-phase response factor


Mass: 68181.125 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STAT3, APRF / Production host: Escherichia coli (E. coli) / References: UniProt: P40763
#2: Antibody Monobody


Mass: 10195.304 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 4.78 Å3/Da / Density % sol: 74.25 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 19% PEG300 70mM Calcium acetate dihydrate 100mM imidazole pH = 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: May 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→49.78 Å / Num. obs: 68863 / % possible obs: 99.9 % / Redundancy: 26.6 % / Biso Wilson estimate: 80.93 Å2 / CC1/2: 0.998 / Net I/σ(I): 10.3
Reflection shellResolution: 2.9→2.97 Å / Num. unique obs: 4535 / CC1/2: 0.252 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Starting model: 4.0E+68 / Resolution: 2.9→49.78 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.923 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.462 / ESU R Free: 0.326
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2806 3429 5 %RANDOM
Rwork0.2459 ---
obs0.2476 68566 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 221.24 Å2 / Biso mean: 83.2292 Å2 / Biso min: 35.62 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20 Å2
2---0.01 Å20 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.9→49.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10063 0 0 2 10065
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0210272
X-RAY DIFFRACTIONr_bond_other_d00.029900
X-RAY DIFFRACTIONr_angle_refined_deg1.9351.96413913
X-RAY DIFFRACTIONr_angle_other_deg3.643322828
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.26251248
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.05724.912452
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.036151876
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7291548
X-RAY DIFFRACTIONr_chiral_restr0.1060.21574
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02111437
X-RAY DIFFRACTIONr_gen_planes_other0.010.022279
X-RAY DIFFRACTIONr_mcbond_it7.4688.0745022
X-RAY DIFFRACTIONr_mcbond_other7.4688.0745021
X-RAY DIFFRACTIONr_mcangle_it11.25312.16260
LS refinement shellResolution: 2.901→2.976 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.452 240 -
Rwork0.45 4696 -
all-4936 -
obs--98.92 %

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