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- PDB-9fr5: Crystal structure of human GSK3B in complex with ARN25697 -

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Basic information

Entry
Database: PDB / ID: 9fr5
TitleCrystal structure of human GSK3B in complex with ARN25697
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase inhibitors / multitarget compounds / drug discovery / central nervous system / tauopathies
Function / homology
Function and homology information


negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of mesenchymal stem cell differentiation / negative regulation of type B pancreatic cell development / regulation of protein export from nucleus / 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 glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of mesenchymal stem cell differentiation / negative regulation of type B pancreatic cell development / regulation of protein export from nucleus / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of TORC2 signaling / beta-arrestin-dependent dopamine receptor signaling pathway / negative regulation of dopaminergic neuron differentiation / positive regulation of protein localization to centrosome / maintenance of cell polarity / positive regulation of cilium assembly / heart valve development / CRMPs in Sema3A signaling / 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 / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / negative regulation of calcineurin-NFAT signaling cascade / Maturation of nucleoprotein / 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 / negative regulation of TOR signaling / regulation of long-term synaptic potentiation / Wnt signalosome / regulation of microtubule-based process / AKT phosphorylates targets in the cytosol / Disassembly of the destruction complex and recruitment of AXIN to the membrane / regulation of axon extension / positive regulation of protein binding / regulation of neuron projection development / negative regulation of protein localization to nucleus / Maturation of nucleoprotein / glycogen metabolic process / ER overload response / negative regulation of epithelial to mesenchymal transition / positive regulation of cell-matrix adhesion / tau-protein kinase activity / regulation of axonogenesis / establishment of cell polarity / regulation of dendrite morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / canonical Wnt signaling pathway / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway / negative regulation of osteoblast differentiation / NF-kappaB binding / negative regulation of protein-containing complex assembly / cellular response to retinoic acid / regulation of cellular response to heat / positive regulation of type I interferon production / presynaptic modulation of chemical synaptic transmission / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / positive regulation of protein export from nucleus / negative regulation of cell migration / response to endoplasmic reticulum stress / excitatory postsynaptic potential / positive regulation of protein ubiquitination / hippocampus development / mitochondrion organization / regulation of microtubule cytoskeleton organization / peptidyl-serine phosphorylation / positive regulation of cell differentiation / negative regulation of canonical Wnt signaling pathway / Ubiquitin-dependent degradation of Cyclin D / circadian rhythm / positive regulation of protein-containing complex assembly / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / regulation of circadian rhythm / beta-catenin binding / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / B-WICH complex positively regulates rRNA expression / Wnt signaling pathway / tau protein binding / Degradation of beta-catenin by the destruction complex / cellular response to amyloid-beta / neuron projection development / kinase activity / positive regulation of protein catabolic process / p53 binding / Regulation of RUNX2 expression and activity / insulin receptor signaling pathway / 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: J.Med.Chem. / Year: 2026
Title: A Polypharmacology-Driven Approach to Alzheimer's Disease and Tauopathies: Rational Design, Synthesis and Characterization of Amino-Pyrazole-Based Multikinase (GSK-3 beta /FYN-alpha /DYRK1A) Inhibitors.
Authors: Demuro, S. / Russo, D. / Penna, I. / Grabska, S. / Grabski, H. / Dalle Vedove, A. / Valeri, A. / Sauvey, C. / Ottonello, G. / Summa, M. / Bertozzi, S.M. / Ortega, J. / Bertorelli, R. / ...Authors: Demuro, S. / Russo, D. / Penna, I. / Grabska, S. / Grabski, H. / Dalle Vedove, A. / Valeri, A. / Sauvey, C. / Ottonello, G. / Summa, M. / Bertozzi, S.M. / Ortega, J. / Bertorelli, R. / Storici, P. / Girotto, S. / Cruciani, G. / Di Martino, R.M.C. / Abagyan, R. / Cavalli, A.
History
DepositionJun 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2026Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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

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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)99,2944
Polymers98,5722
Non-polymers7232
Water6,053336
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6472
Polymers49,2861
Non-polymers3611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6472
Polymers49,2861
Non-polymers3611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.370, 85.550, 178.640
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-A1IE8 / ~{N}4-(3-cyclobutyl-1~{H}-pyrazol-5-yl)-~{N}2-(pyridin-3-ylmethyl)furo[3,2-d]pyrimidine-2,4-diamine


Mass: 361.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 336 / 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: 3.36 Å3/Da / Density % sol: 63.42 %
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 PILATUS 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: 2.089→61.783 Å / Num. obs: 75560 / % possible obs: 100 % / Redundancy: 13.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.022 / Net I/σ(I): 19.3
Reflection shellResolution: 2.089→2.125 Å / Num. unique obs: 3715 / CC1/2: 0.857

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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→61.78 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.06 / 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
Rfree0.2351 2925 5.15 %
Rwork0.2019 --
obs0.2037 56762 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→61.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5668 0 54 336 6058
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025872
X-RAY DIFFRACTIONf_angle_d0.6097986
X-RAY DIFFRACTIONf_dihedral_angle_d12.023804
X-RAY DIFFRACTIONf_chiral_restr0.042887
X-RAY DIFFRACTIONf_plane_restr0.0051025
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.340.29141150.25772423X-RAY DIFFRACTION96
2.34-2.380.26181150.25862612X-RAY DIFFRACTION100
2.38-2.420.30671040.24392542X-RAY DIFFRACTION100
2.42-2.470.2731440.22972524X-RAY DIFFRACTION100
2.47-2.520.2791430.23442529X-RAY DIFFRACTION100
2.52-2.570.27411370.21362542X-RAY DIFFRACTION100
2.57-2.630.22961250.2192545X-RAY DIFFRACTION100
2.63-2.70.26161430.21032542X-RAY DIFFRACTION100
2.7-2.770.24011410.22372543X-RAY DIFFRACTION100
2.77-2.850.25371480.23042537X-RAY DIFFRACTION100
2.85-2.950.27791510.23882537X-RAY DIFFRACTION100
2.95-3.050.28311340.22772567X-RAY DIFFRACTION100
3.05-3.170.22961310.22222561X-RAY DIFFRACTION100
3.17-3.320.26221540.21632533X-RAY DIFFRACTION100
3.32-3.490.24831370.21042570X-RAY DIFFRACTION100
3.49-3.710.19481260.20842605X-RAY DIFFRACTION100
3.71-40.23611530.18412546X-RAY DIFFRACTION100
4-4.40.211580.16712589X-RAY DIFFRACTION100
4.4-5.040.18371710.15982582X-RAY DIFFRACTION100
5.04-6.340.27231290.20482668X-RAY DIFFRACTION100
6.34-61.780.20461660.16712740X-RAY DIFFRACTION100

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