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

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Basic information

Entry
Database: PDB / ID: 8djc
TitleCRYSTAL STRUCTURE OF GLYCOGEN SYNTHASE KINASE 3 BETA COMPLEXED WITH (4S)-N-{4-[(2S)-2-methylmorpholin-4-yl] pyridin-3-yl}-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE/INHIBITOR / KINASE / GSK3B / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium ...regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of dopaminergic neuron differentiation / positive regulation of protein localization to centrosome / maintenance of cell polarity / positive regulation of cilium assembly / negative regulation of protein acetylation / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / beta-catenin destruction complex / tau-protein kinase / CRMPs in Sema3A signaling / heart valve development / 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 / Maturation of nucleoprotein / cellular response to interleukin-3 / negative regulation of TOR signaling / Wnt signalosome / negative regulation of protein localization to nucleus / regulation of long-term synaptic potentiation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / negative regulation of epithelial to mesenchymal transition / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / G protein-coupled dopamine receptor signaling pathway / regulation of axonogenesis / regulation of dendrite morphogenesis / tau-protein kinase activity / establishment of cell polarity / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / NF-kappaB binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / canonical Wnt signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / presynaptic modulation of chemical synaptic transmission / positive regulation of GTPase activity / positive regulation of protein export from nucleus / excitatory postsynaptic potential / negative regulation of cell migration / positive regulation of protein ubiquitination / hippocampus development / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / peptidyl-threonine phosphorylation / positive regulation of cell differentiation / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / positive regulation of protein-containing complex assembly / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / regulation of circadian rhythm / negative regulation of canonical Wnt signaling pathway / tau protein binding / Degradation of beta-catenin by the destruction complex / B-WICH complex positively regulates rRNA expression / beta-catenin binding / circadian rhythm / positive regulation of protein catabolic process / cellular response to amyloid-beta / Regulation of RUNX2 expression and activity / neuron projection development / p53 binding / positive regulation of protein binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / insulin receptor signaling pathway / 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
Chem-UAU / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.463 Å
AuthorsLewis, H.A. / Muckelbauer, J.K.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2- b ]pyridazines as Glycogen Synthase Kinase-3 beta (GSK-3 beta ) Inhibitors.
Authors: Hartz, R.A. / Ahuja, V.T. / Sivaprakasam, P. / Xiao, H. / Krause, C.M. / Clarke, W.J. / Kish, K. / Lewis, H. / Szapiel, N. / Ravirala, R. / Mutalik, S. / Nakmode, D. / Shah, D. / Burton, C.R. ...Authors: Hartz, R.A. / Ahuja, V.T. / Sivaprakasam, P. / Xiao, H. / Krause, C.M. / Clarke, W.J. / Kish, K. / Lewis, H. / Szapiel, N. / Ravirala, R. / Mutalik, S. / Nakmode, D. / Shah, D. / Burton, C.R. / Macor, J.E. / Dubowchik, G.M.
History
DepositionJun 30, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)99,4194
Polymers98,5902
Non-polymers8292
Water1,45981
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,7092
Polymers49,2951
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,7092
Polymers49,2951
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.979, 86.003, 178.482
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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-UAU / (4S)-N-{4-[(2S)-2-methylmorpholin-4-yl]pyridin-3-yl}-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide


Mass: 414.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 81 / 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: 3.23 Å3/Da / Density % sol: 61.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M MES pH 6.0, 20.0 %w/v PEG6K, 0.2 M NH4Cl

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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 23, 2016 / Details: Kirkpatrick-Baez Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.46→89.24 Å / Num. obs: 41287 / % possible obs: 87.6 % / Redundancy: 6.6 % / Biso Wilson estimate: 57.66 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.047 / Rrim(I) all: 0.121 / Net I/σ(I): 11.9 / Num. measured all: 271227
Reflection shellResolution: 2.46→2.59 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.741 / Mean I/σ(I) obs: 2.2 / Num. measured all: 43856 / Num. unique obs: 6776 / CC1/2: 0.86 / Rpim(I) all: 0.349 / Rrim(I) all: 0.892 / Net I/σ(I) obs: 2.2 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTERrefinement
Aimless0.5.27data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished model

Resolution: 2.463→24.82 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.903 / SU R Cruickshank DPI: 0.283 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.275 / SU Rfree Blow DPI: 0.217 / SU Rfree Cruickshank DPI: 0.222
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2419 2003 4.87 %RANDOM
Rwork0.2156 ---
obs0.2168 41160 87.7 %-
Displacement parametersBiso max: 95.78 Å2 / Biso mean: 48.87 Å2 / Biso min: 26.89 Å2
Baniso -1Baniso -2Baniso -3
1--4.0657 Å20 Å20 Å2
2---10.6706 Å20 Å2
3---14.7363 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.463→24.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5090 0 62 81 5233
Biso mean--43.96 42.82 -
Num. residues----663
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1716SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes952HARMONIC5
X-RAY DIFFRACTIONt_it5287HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion713SEMIHARMONIC5
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_contact3899SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5331HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7331HARMONIC20.9
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion16.95
LS refinement shellResolution: 2.463→2.48 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3155 37 4.49 %
Rwork0.2973 787 -
obs--100 %

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