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- PDB-9hv3: Crystal structure of human GSK3b in complex with ARN25657 -

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Basic information

Entry
Database: PDB / ID: 9hv3
TitleCrystal structure of human GSK3b in complex with ARN25657
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase inhibitors / multitarget compounds / drug discovery / bipolar disorder
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 / beta-catenin destruction complex / CRMPs in Sema3A signaling / heart valve development / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / tau-protein kinase / regulation of microtubule-based process / regulation of protein export from nucleus / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / cellular response to interleukin-3 / Wnt signalosome / regulation of long-term synaptic potentiation / negative regulation of TOR signaling / negative regulation of protein localization to nucleus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / AKT phosphorylates targets in the cytosol / negative regulation of calcineurin-NFAT signaling cascade / regulation of axon extension / Maturation of nucleoprotein / tau-protein kinase activity / G protein-coupled dopamine receptor signaling pathway / negative regulation of epithelial to mesenchymal transition / positive regulation of cell-matrix adhesion / regulation of axonogenesis / regulation of dendrite morphogenesis / glycogen metabolic process / ER overload response / regulation of neuron projection development / establishment of cell polarity / protein kinase A catalytic subunit binding / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / NF-kappaB binding / canonical Wnt signaling pathway / negative regulation of protein-containing complex assembly / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / 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 / presynaptic modulation of chemical synaptic transmission / Transcriptional and post-translational regulation of MITF-M expression and activity / regulation of microtubule cytoskeleton organization / response to endoplasmic reticulum stress / negative regulation of cell migration / positive regulation of protein export from nucleus / hippocampus development / positive regulation of protein ubiquitination / excitatory postsynaptic potential / Ubiquitin-dependent degradation of Cyclin D / mitochondrion organization / positive regulation of cell differentiation / positive regulation of protein-containing complex assembly / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H2AS121 kinase activity / histone H3S57 kinase activity / eukaryotic translation initiation factor 2alpha kinase activity / histone H3S28 kinase activity / histone H2AS1 kinase activity / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / negative regulation of canonical Wnt signaling pathway / histone H3T6 kinase activity / ribosomal protein S6 kinase activity / histone H2AT120 kinase activity / histone H2BS36 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3S10 kinase activity / AMP-activated protein kinase activity / 3-phosphoinositide-dependent protein kinase activity / histone H3T11 kinase activity / histone H3T3 kinase activity / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / histone H3T45 kinase activity
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: 2.9 Å
AuthorsDalle Vedove, A. / Di Martino, R.M.C. / Storici, P. / Girotto, S. / Cavalli, A. / Bottegoni, G.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: Eur.J.Med.Chem. / Year: 2025
Title: Rational optimization of D3R/GSK-3 beta dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in ...Title: Rational optimization of D3R/GSK-3 beta dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in vitro ADME, and in vivo pharmacokinetic studies.
Authors: Di Martino, R.M.C. / Russo, D. / Penna, I. / Demuro, S. / Dalle Vedove, A. / Spagnuolo, R. / Ottonello, G. / Bertozzi, S.M. / Summa, M. / Desantis, J. / Valeri, A. / Pruccoli, L. / Tripathi, ...Authors: Di Martino, R.M.C. / Russo, D. / Penna, I. / Demuro, S. / Dalle Vedove, A. / Spagnuolo, R. / Ottonello, G. / Bertozzi, S.M. / Summa, M. / Desantis, J. / Valeri, A. / Pruccoli, L. / Tripathi, S.K. / Tarozzi, A. / Storici, P. / Girotto, S. / Bertorelli, R. / Armirotti, A. / Cruciani, G. / Bandiera, T. / Cavalli, A. / Bottegoni, G.
History
DepositionDec 24, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 23, 2025Provider: 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)99,4854
Polymers98,5722
Non-polymers9132
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2670 Å2
ΔGint-11 kcal/mol
Surface area33690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.474, 85.620, 178.340
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-A1IXN / 2-oxidanylidene-~{N}-[3-(4-phenylpiperazin-1-yl)propyl]-6-pyridin-3-yl-3~{H}-benzimidazole-1-carboxamide


Mass: 456.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
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: 3.19 Å3/Da / Density % sol: 61.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion / 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 PILATUS 6M / Detector: PIXEL / Date: Feb 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→60.55 Å / Num. obs: 28728 / % possible obs: 99.87 % / Redundancy: 2 % / CC1/2: 0.999 / Net I/σ(I): 17.4
Reflection shellResolution: 2.9→3.004 Å / Num. unique obs: 2815 / CC1/2: 0.924

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7U36

7u36


Resolution: 2.9→60.55 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2376 2003 6.98 %
Rwork0.2061 --
obs0.2083 28702 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→60.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5750 0 68 0 5818
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095968
X-RAY DIFFRACTIONf_angle_d0.9948111
X-RAY DIFFRACTIONf_dihedral_angle_d14.1282255
X-RAY DIFFRACTIONf_chiral_restr0.056896
X-RAY DIFFRACTIONf_plane_restr0.0111039
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.970.34531390.3021893X-RAY DIFFRACTION100
2.97-3.050.33751380.26791882X-RAY DIFFRACTION100
3.05-3.140.27671460.24061854X-RAY DIFFRACTION100
3.14-3.240.33781370.23281866X-RAY DIFFRACTION100
3.24-3.360.2551370.21571877X-RAY DIFFRACTION100
3.36-3.490.23511440.21961887X-RAY DIFFRACTION100
3.49-3.650.27791390.23391885X-RAY DIFFRACTION100
3.65-3.850.25631450.22261896X-RAY DIFFRACTION100
3.85-4.090.21161330.2051915X-RAY DIFFRACTION100
4.09-4.40.1941470.17051906X-RAY DIFFRACTION100
4.4-4.850.22551400.1771915X-RAY DIFFRACTION100
4.85-5.550.23291480.19921923X-RAY DIFFRACTION100
5.55-6.990.24311530.21821951X-RAY DIFFRACTION100
6.99-60.550.19411570.18192049X-RAY DIFFRACTION99

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