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- PDB-9fr6: Crystal structure of human GSK3B in complex with ARN25641 -

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Basic information

Entry
Database: PDB / ID: 9fr6
TitleCrystal structure of human GSK3B in complex with ARN25641
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase inhibitors / multitarget compounds / drug discovery / central nervous system / tauopathies
Function / homology
Function and homology information


neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of type B pancreatic cell development / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of TORC2 signaling / negative regulation of dopaminergic neuron differentiation ...neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of type B pancreatic cell development / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of TORC2 signaling / negative regulation of dopaminergic neuron differentiation / maintenance of cell polarity / positive regulation of protein localization to centrosome / positive regulation of cilium assembly / CRMPs in Sema3A signaling / heart valve development / tau-protein kinase / beta-catenin destruction complex / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / regulation of protein export from nucleus / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / cellular response to interleukin-3 / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / Maturation of nucleoprotein / Wnt signalosome / regulation of long-term synaptic potentiation / negative regulation of TOR signaling / negative regulation of protein localization to nucleus / regulation of microtubule-based process / AKT phosphorylates targets in the cytosol / Disassembly of the destruction complex and recruitment of AXIN to the membrane / negative regulation of calcineurin-NFAT signaling cascade / regulation of axon extension / Maturation of nucleoprotein / negative regulation of epithelial to mesenchymal transition / tau-protein kinase activity / positive regulation of cell-matrix adhesion / regulation of axonogenesis / G protein-coupled dopamine receptor signaling pathway / glycogen metabolic process / ER overload response / regulation of dendrite morphogenesis / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / establishment of cell polarity / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / canonical Wnt signaling pathway / NF-kappaB binding / negative regulation of osteoblast differentiation / positive regulation of protein binding / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of protein-containing complex assembly / regulation of cellular response to heat / extrinsic apoptotic signaling pathway / cellular response to retinoic acid / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of autophagy / Transcriptional and post-translational regulation of MITF-M expression and activity / presynaptic modulation of chemical synaptic transmission / regulation of microtubule cytoskeleton organization / negative regulation of cell migration / response to endoplasmic reticulum stress / positive regulation of protein ubiquitination / positive regulation of protein export from nucleus / excitatory postsynaptic potential / mitochondrion organization / hippocampus development / Ubiquitin-dependent degradation of Cyclin D / positive regulation of cell differentiation / positive regulation of protein-containing complex assembly / negative regulation of canonical Wnt signaling pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / circadian rhythm / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / beta-catenin binding / peptidyl-serine phosphorylation / regulation of circadian rhythm / Degradation of beta-catenin by the destruction complex / B-WICH complex positively regulates rRNA expression / tau protein binding / cellular response to amyloid-beta / Wnt signaling pathway / neuron projection development / Regulation of RUNX2 expression and activity / p53 binding / positive regulation of protein catabolic process / kinase activity / insulin receptor signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of neuron apoptotic process
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsDalle Vedove, A. / Demuro, S. / Di Martino, R.M.C. / Balboni, B. / Tripathi, S.K. / Storici, P. / Girotto, S. / Cavalli, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM1311991 United States
CitationJournal: To Be Published
Title: Unveiling the pharmacophoric traits of balanced triple GSK-3B/FYN/DYRK1A inhibitors: rational design and synthesis of novel amino-pyrazole containing scaffolds for the treatment of Alzheimer's ...Title: Unveiling the pharmacophoric traits of balanced triple GSK-3B/FYN/DYRK1A inhibitors: rational design and synthesis of novel amino-pyrazole containing scaffolds for the treatment of Alzheimer's disease and related tauopathies.
Authors: Demuro, S.
History
DepositionJun 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glycogen synthase kinase-3 beta
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,3834
Polymers98,5722
Non-polymers8112
Water5,008278
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6912
Polymers49,2861
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6912
Polymers49,2861
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.310, 85.260, 178.440
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glycogen synthase kinase-3 beta / GSK-3 beta / Serine/threonine-protein kinase GSK3B


Mass: 49285.793 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1IFO / 3-[[[4-[(3-cyclopropyl-1~{H}-pyrazol-5-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]methyl]benzamide


Mass: 405.476 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C20H19N7OS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 3.34 Å3/Da / Density % sol: 63.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.4 / Details: PEG3350, Sodium Chloride, Hepes

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 18, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.181→74.742 Å / Num. obs: 66122 / % possible obs: 99.9 % / Redundancy: 13 % / CC1/2: 0.999 / Rpim(I) all: 0.026 / Net I/σ(I): 16
Reflection shellResolution: 2.181→2.219 Å / Num. unique obs: 3182 / CC1/2: 0.082 / Rpim(I) all: 0.423

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→74.74 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.62 / Stereochemistry target values: ML
Details: The data were first treated with Starniso and then cut at the highest resolution with elliptical completeness >90%, CC1/2 >90% e I/sigma >2
RfactorNum. reflection% reflection
Rfree0.232 2649 4.84 %
Rwork0.1986 --
obs0.2002 54783 96.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→74.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5668 0 58 278 6004
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0045876
X-RAY DIFFRACTIONf_angle_d0.6487994
X-RAY DIFFRACTIONf_dihedral_angle_d12.443802
X-RAY DIFFRACTIONf_chiral_restr0.044887
X-RAY DIFFRACTIONf_plane_restr0.0061027
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.340.2841250.25192239X-RAY DIFFRACTION81
2.34-2.390.28661390.23892299X-RAY DIFFRACTION83
2.39-2.440.29851300.23152436X-RAY DIFFRACTION87
2.44-2.490.29351230.22992518X-RAY DIFFRACTION91
2.49-2.550.27861250.21912740X-RAY DIFFRACTION98
2.55-2.610.27971280.21942831X-RAY DIFFRACTION100
2.61-2.680.28071180.20992840X-RAY DIFFRACTION100
2.68-2.760.26651750.21872771X-RAY DIFFRACTION100
2.76-2.850.25961420.23022808X-RAY DIFFRACTION100
2.85-2.950.30911420.24442822X-RAY DIFFRACTION100
2.95-3.070.24691360.23242817X-RAY DIFFRACTION100
3.07-3.210.25291420.21582825X-RAY DIFFRACTION100
3.21-3.380.24651510.21082816X-RAY DIFFRACTION100
3.38-3.590.2441550.20952837X-RAY DIFFRACTION100
3.59-3.870.21371250.19532846X-RAY DIFFRACTION100
3.87-4.260.20071380.17022869X-RAY DIFFRACTION100
4.26-4.870.16511620.15282859X-RAY DIFFRACTION100
4.87-6.140.22261400.19732918X-RAY DIFFRACTION100
6.14-74.740.20541530.17173043X-RAY DIFFRACTION100

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