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- PDB-9rl6: Structure Guided Optimisation of Niclosamide Derivatives as Direc... -

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Basic information

Entry
Database: PDB / ID: 9rl6
TitleStructure Guided Optimisation of Niclosamide Derivatives as Direct STAT3 Inhibitors Targeting a Novel Binding Site
Components
  • DNA (5'-D(*TP*GP*CP*AP*TP*TP*TP*CP*CP*CP*GP*TP*AP*AP*AP*TP*CP*T)-3')
  • Isoform Stat3B of Signal transducer and activator of transcription 3
KeywordsDNA BINDING PROTEIN / SH2 Domain / Protein DNA Complex / Signal Transducer / Activator of Transcription / Duplex DNA / Nucleus / Cytosol / TRANSCRIPTION-DNA complex
Function / homology
Function and homology information


STAT3 nuclear events downstream of ALK signaling / MET activates STAT3 / Interleukin-37 signaling / Interleukin-10 signaling / PTK6 Activates STAT3 / Signaling by ALK / Interleukin-21 signaling / Interleukin-9 signaling / Interleukin-4 and Interleukin-13 signaling / Interleukin-15 signaling ...STAT3 nuclear events downstream of ALK signaling / MET activates STAT3 / Interleukin-37 signaling / Interleukin-10 signaling / PTK6 Activates STAT3 / Signaling by ALK / Interleukin-21 signaling / Interleukin-9 signaling / Interleukin-4 and Interleukin-13 signaling / Interleukin-15 signaling / RNA sequestering activity / negative regulation of 3'-UTR-mediated mRNA stabilization / Interleukin-20 family signaling / Interleukin-23 signaling / Interleukin-27 signaling / eye photoreceptor cell differentiation / radial glial cell differentiation / Interleukin-6 signaling / negative regulation of primary miRNA processing / Downstream signal transduction / Interleukin-35 Signalling / Interleukin-7 signaling / Signaling by SCF-KIT / leptin-mediated signaling pathway / negative regulation of hydrogen peroxide biosynthetic process / T-helper 17 type immune response / negative regulation of neuron migration / PKR-mediated signaling / regulation of feeding behavior / positive regulation of extracellular matrix disassembly / primary miRNA binding / interleukin-11-mediated signaling pathway / negative regulation of inflammatory response to wounding / CCR5 chemokine receptor binding / cellular response to interleukin-17 / response to leptin / T-helper 17 cell lineage commitment / interleukin-9-mediated signaling pathway / inflammatory response to wounding / interleukin-10-mediated signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / nuclear glucocorticoid receptor binding / regulation of cellular response to hypoxia / acetylation-dependent protein binding / interleukin-15-mediated signaling pathway / interleukin-23-mediated signaling pathway / cellular response to leptin stimulus / negative regulation of stem cell differentiation / postsynapse to nucleus signaling pathway / astrocyte differentiation / signal transduction involved in regulation of gene expression / cell surface receptor signaling pathway via STAT / positive regulation of cytokine production involved in inflammatory response / regulation of mitochondrial membrane permeability / positive regulation of vascular endothelial cell proliferation / negative regulation of glycolytic process / growth hormone receptor signaling pathway / interleukin-6-mediated signaling pathway / interleukin-2-mediated signaling pathway / positive regulation of Notch signaling pathway / stem cell population maintenance / eating behavior / cellular response to cytokine stimulus / lncRNA binding / negative regulation of intrinsic apoptotic signaling pathway / temperature homeostasis / positive regulation of ATP biosynthetic process / positive regulation of interleukin-10 production / growth hormone receptor signaling pathway via JAK-STAT / regulation of multicellular organism growth / positive regulation of vascular endothelial growth factor production / cell surface receptor signaling pathway via JAK-STAT / cellular response to hormone stimulus / intracellular receptor signaling pathway / energy homeostasis / endoplasmic reticulum unfolded protein response / canonical NF-kappaB signal transduction / negative regulation of cytokine production involved in inflammatory response / response to cytokine / transforming growth factor beta receptor signaling pathway / signaling adaptor activity / positive regulation of erythrocyte differentiation / positive regulation of phagocytosis / response to ischemia / acute-phase response / negative regulation of autophagy / positive regulation of interleukin-8 production / positive regulation of interleukin-1 beta production / negative regulation of canonical NF-kappaB signal transduction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein sequestering activity / defense response / chromatin DNA binding / positive regulation of miRNA transcription / mRNA transcription by RNA polymerase II / positive regulation of interleukin-6 production / modulation of chemical synaptic transmission / nuclear receptor activity / negative regulation of inflammatory response / response to peptide hormone
Similarity search - Function
STAT3, SH2 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 ...STAT3, SH2 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 / p53-like transcription factor, DNA-binding / SH2 domain / Src homology 2 (SH2) domain profile. / SH2 domain / SH2 domain superfamily
Similarity search - Domain/homology
Chem-VUT / DNA / DNA (> 10) / Signal transducer and activator of transcription 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsQuamruzzaman, M. / Maneshi, P. / Knight, R. / Parkinson, G.N. / Wells, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Structure Guided Optimisation of Niclosamide Derivatives as Direct STAT3 Inhibitors Targeting a Novel Binding Site
Authors: Quamruzzaman, M. / Maneshi, P. / Knight, R. / Parkinson, G.N. / Wells, G.
History
DepositionJun 16, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 24, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: DNA (5'-D(*TP*GP*CP*AP*TP*TP*TP*CP*CP*CP*GP*TP*AP*AP*AP*TP*CP*T)-3')
A: Isoform Stat3B of Signal transducer and activator of transcription 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,9043
Polymers73,5772
Non-polymers3271
Water2,630146
1
B: DNA (5'-D(*TP*GP*CP*AP*TP*TP*TP*CP*CP*CP*GP*TP*AP*AP*AP*TP*CP*T)-3')
A: Isoform Stat3B of Signal transducer and activator of transcription 3
hetero molecules

B: DNA (5'-D(*TP*GP*CP*AP*TP*TP*TP*CP*CP*CP*GP*TP*AP*AP*AP*TP*CP*T)-3')
A: Isoform Stat3B of Signal transducer and activator of transcription 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,8086
Polymers147,1534
Non-polymers6542
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation6_665-x+1,-y+1,z1
Unit cell
Length a, b, c (Å)174.263, 174.263, 78.762
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number80
Space group name H-MI41

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Components

#1: DNA chain DNA (5'-D(*TP*GP*CP*AP*TP*TP*TP*CP*CP*CP*GP*TP*AP*AP*AP*TP*CP*T)-3')


Mass: 5441.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: TOP STRAND M67 / Source: (synth.) Homo sapiens (human)
#2: Protein Isoform Stat3B of Signal transducer and activator of transcription 3 / Acute-phase response factor


Mass: 68135.125 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Stat3, Aprf / Plasmid: PET-32A (+) / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): ROSETTA / References: UniProt: P42227
#3: Chemical ChemComp-VUT / 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide / Niclosamide


Mass: 327.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H8Cl2N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 3.79 Å3/Da / Density % sol: 67.5 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 8% Ethylene Glycol, 0.1M HEPES, 10% PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 1.00667 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00667 Å / Relative weight: 1
ReflectionResolution: 2.38→123.3 Å / Num. obs: 47560 / % possible obs: 100 % / Redundancy: 8 % / CC1/2: 1 / Rmerge(I) obs: 0.081 / Net I/σ(I): 12.2
Reflection shellResolution: 2.38→2.42 Å / Redundancy: 8.2 % / Rmerge(I) obs: 2.91 / Num. unique obs: 2461 / CC1/2: 0.4 / % possible all: 99.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
xia2data reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.55→123.223 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.934 / Cross valid method: FREE R-VALUE / ESU R: 0.324 / ESU R Free: 0.246
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.2494 1847 4.951 %0
Rwork0.2155 35456 --
all0.217 ---
obs-37303 96.462 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 87.41 Å2
Baniso -1Baniso -2Baniso -3
1-0.354 Å20 Å20 Å2
2--0.354 Å20 Å2
3----0.708 Å2
Refinement stepCycle: LAST / Resolution: 2.55→123.223 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4499 360 21 146 5026
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0125009
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164677
X-RAY DIFFRACTIONr_angle_refined_deg1.5081.6566841
X-RAY DIFFRACTIONr_angle_other_deg0.821.56610797
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4895556
X-RAY DIFFRACTIONr_dihedral_angle_2_deg15.6345.6929
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg0.943511
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.96410869
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.82110209
X-RAY DIFFRACTIONr_chiral_restr0.0670.2767
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025497
X-RAY DIFFRACTIONr_gen_planes_other0.0070.021106
X-RAY DIFFRACTIONr_nbd_refined0.2530.21170
X-RAY DIFFRACTIONr_symmetry_nbd_other0.240.24544
X-RAY DIFFRACTIONr_nbtor_refined0.1940.22413
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0860.22697
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1960.2176
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1410.29
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.3480.234
X-RAY DIFFRACTIONr_nbd_other0.3570.2169
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2830.240
X-RAY DIFFRACTIONr_mcbond_it9.3479.0632233
X-RAY DIFFRACTIONr_mcbond_other9.3469.0632233
X-RAY DIFFRACTIONr_mcangle_it13.84916.2462786
X-RAY DIFFRACTIONr_mcangle_other13.84816.2492787
X-RAY DIFFRACTIONr_scbond_it8.9458.9922776
X-RAY DIFFRACTIONr_scbond_other8.9448.9922777
X-RAY DIFFRACTIONr_scangle_it13.75416.3244055
X-RAY DIFFRACTIONr_scangle_other13.67416.3214055
X-RAY DIFFRACTIONr_lrange_it19.737103.25620538
X-RAY DIFFRACTIONr_lrange_other19.751103.24320478
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.55-2.6160.457930.43116350.43328250.9060.91961.16810.426
2.616-2.6880.4641370.39123740.39527730.9050.93590.55180.383
2.688-2.7660.3981580.34325330.34626910.9360.9471000.33
2.766-2.8510.3521150.31624990.31826140.9340.9491000.294
2.851-2.9440.3511370.28624390.28925760.9270.9561000.257
2.944-3.0480.2651110.24923020.24924140.9520.96399.95860.218
3.048-3.1630.2461120.22322800.22423920.9610.971000.196
3.163-3.2920.2921200.2121550.21422750.9430.9751000.186
3.292-3.4380.2581270.22520520.22721790.9640.9721000.207
3.438-3.6050.243810.22420430.22521240.9630.9751000.209
3.605-3.80.2791130.22518890.22720020.9560.9751000.216
3.8-4.0310.291970.20617660.2118630.9550.9761000.2
4.031-4.3090.2191050.19516850.19617900.9660.9781000.196
4.309-4.6530.206740.1815870.18116620.9750.9899.93980.189
4.653-5.0970.173600.16714570.16815170.9820.9821000.183
5.097-5.6970.244560.1813440.18314000.970.9821000.197
5.697-6.5760.22410.21811850.21912260.9720.9741000.234
6.576-8.0480.175580.2089960.20610550.9820.97599.90520.237
8.048-11.3580.166400.1547760.1548160.9820.9851000.188
11.358-123.2230.403120.284590.2824750.8910.90799.15790.462

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