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- PDB-8ff8: CRYSTAL STRUCTURE OF GLYCOGEN SYNTHASE KINASE 3 BETA COMPLEXED WI... -

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Basic information

Entry
Database: PDB / ID: 8ff8
TitleCRYSTAL STRUCTURE OF GLYCOGEN SYNTHASE KINASE 3 BETA COMPLEXED WITH 2-[(4-CYANOPHENYL)AMINO]-N-(4-PHENYLPYRIDIN-3-YL)PYRIMIDINE-4-CARBOXAMIDE
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE/INHIBITOR / GSK3beta / kinase / ligand inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
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 / 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 / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / negative regulation of epithelial to mesenchymal transition / G protein-coupled dopamine receptor signaling pathway / positive regulation of cell-matrix adhesion / regulation of axonogenesis / regulation of dendrite morphogenesis / ER overload response / glycogen metabolic process / establishment of cell polarity / regulation of neuron projection development / 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 / canonical Wnt signaling pathway / NF-kappaB binding / positive regulation of protein binding / 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 / positive regulation of protein ubiquitination / 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 / Ubiquitin-dependent degradation of Cyclin D / response to endoplasmic reticulum stress / negative regulation of cell migration / histone H4S1 kinase activity / : / histone H3S57 kinase activity / histone H2BS14 kinase activity / histone H3S28 kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / ribosomal protein S6 kinase activity / histone H2AT120 kinase activity / histone H2BS36 kinase activity / eukaryotic translation initiation factor 2alpha kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3S10 kinase activity / positive regulation of protein export from nucleus / AMP-activated protein kinase activity / histone H3T11 kinase activity / hippocampus development / histone H3T3 kinase activity / 3-phosphoinositide-dependent protein kinase activity / histone H3T45 kinase activity / excitatory postsynaptic potential / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / mitochondrion organization
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
Chem-XV0 / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsMuckelbauer, J.K. / Lewis, H.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.
Authors: Hartz, R.A. / Ahuja, V.T. / Luo, G. / Chen, L. / Sivaprakasam, P. / Xiao, H. / Krause, C.M. / Clarke, W.J. / Xu, S. / Tokarski, J.S. / Kish, K. / Lewis, H. / Szapiel, N. / Ravirala, R. / ...Authors: Hartz, R.A. / Ahuja, V.T. / Luo, G. / Chen, L. / Sivaprakasam, P. / Xiao, H. / Krause, C.M. / Clarke, W.J. / Xu, S. / Tokarski, J.S. / Kish, K. / Lewis, H. / Szapiel, N. / Ravirala, R. / Mutalik, S. / Nakmode, D. / Shah, D. / Burton, C.R. / Macor, J.E. / Dubowchik, G.M.
History
DepositionDec 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)99,3744
Polymers98,5902
Non-polymers7852
Water4,089227
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6872
Polymers49,2951
Non-polymers3921
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6872
Polymers49,2951
Non-polymers3921
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.843, 84.083, 177.788
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: 49294.828 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-XV0 / 2-(4-cyanoanilino)-N-(4-phenylpyridin-3-yl)pyrimidine-4-carboxamide


Mass: 392.413 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H16N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.14 Å3/Da / Density % sol: 60.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES pH 6.0, 20.0 %w/v PEG6K, 0.2 M NH4Cl, 293K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.33→88.89 Å / Num. obs: 50145 / % possible obs: 92.6 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.076 / Net I/σ(I): 15.8
Reflection shellResolution: 2.33→2.46 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.635 / Num. unique obs: 7784 / % possible all: 99.9

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Processing

Software
NameClassification
BUSTERrefinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.33→88.89 Å / Cor.coef. Fo:Fc: 0.887 / Cor.coef. Fo:Fc free: 0.876 / SU R Cruickshank DPI: 0.212 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.213 / SU Rfree Blow DPI: 0.172 / SU Rfree Cruickshank DPI: 0.173
RfactorNum. reflection% reflectionSelection details
Rfree0.2171 2440 4.87 %RANDOM
Rwork0.1966 ---
obs0.1976 50071 92.6 %-
Displacement parametersBiso mean: 51.67 Å2
Baniso -1Baniso -2Baniso -3
1-0.8377 Å20 Å20 Å2
2---26.3788 Å20 Å2
3---25.5411 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 2.33→88.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5335 0 60 230 5625
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085572HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.97648HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1778SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1019HARMONIC5
X-RAY DIFFRACTIONt_it5540HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.18
X-RAY DIFFRACTIONt_other_torsion17.77
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion740SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4530SEMIHARMONIC4
LS refinement shellResolution: 2.33→2.34 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2472 -5.19 %
Rwork0.2469 950 -
all0.247 1002 -
obs--99.61 %

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