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- PDB-6b8j: Co-structure of human glycogen synthase kinase beta with a select... -

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Basic information

Entry
Database: PDB / ID: 6b8j
TitleCo-structure of human glycogen synthase kinase beta with a selective (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine inhibitor
Components
  • Glycogen synthase kinase-3 beta
  • VAL-SEP-ARG-ARG
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / kinase / TRANSFERASE / TRANSFERASE-TRANSFERASE Inhibitor complex
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 / 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 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 / 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 / CRMPs in Sema3A signaling / tau-protein kinase / heart valve development / 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 / regulation of protein export from nucleus / cellular response to interleukin-3 / Maturation of nucleoprotein / 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 / regulation of long-term synaptic potentiation / Wnt signalosome / negative regulation of TOR signaling / regulation of microtubule-based process / AKT phosphorylates targets in the cytosol / Disassembly of the destruction complex and recruitment of AXIN to the membrane / positive regulation of protein binding / regulation of axon extension / negative regulation of calcineurin-NFAT signaling cascade / Maturation of nucleoprotein / negative regulation of protein localization to nucleus / negative regulation of epithelial to mesenchymal transition / tau-protein kinase activity / positive regulation of cell-matrix adhesion / glycogen metabolic process / ER overload response / regulation of axonogenesis / 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 / negative regulation of osteoblast differentiation / NF-kappaB 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 type I interferon production / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / response to endoplasmic reticulum stress / negative regulation of cell migration / positive regulation of protein export from nucleus / presynaptic modulation of chemical synaptic transmission / positive regulation of protein ubiquitination / peptidyl-serine phosphorylation / regulation of microtubule cytoskeleton organization / hippocampus development / positive regulation of cell differentiation / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / positive regulation of protein-containing complex assembly / excitatory postsynaptic potential / negative regulation of canonical Wnt signaling pathway / circadian rhythm / regulation of circadian rhythm / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / B-WICH complex positively regulates rRNA expression / beta-catenin binding / Degradation of beta-catenin by the destruction complex / tau protein binding / cellular response to amyloid-beta / Wnt signaling pathway / neuron projection development / kinase activity / p53 binding / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / insulin receptor signaling pathway / protein autophosphorylation
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Glycogen synthase kinase 3, catalytic domain / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
CHIR99021 / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.595 Å
AuthorsBussiere, D.E.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3.
Authors: Wagman, A.S. / Boyce, R.S. / Brown, S.P. / Fang, E. / Goff, D. / Jansen, J.M. / Le, V.P. / Levine, B.H. / Ng, S.C. / Ni, Z.J. / Nuss, J.M. / Pfister, K.B. / Ramurthy, S. / Renhowe, P.A. / ...Authors: Wagman, A.S. / Boyce, R.S. / Brown, S.P. / Fang, E. / Goff, D. / Jansen, J.M. / Le, V.P. / Levine, B.H. / Ng, S.C. / Ni, Z.J. / Nuss, J.M. / Pfister, K.B. / Ramurthy, S. / Renhowe, P.A. / Ring, D.B. / Shu, W. / Subramanian, S. / Zhou, X.A. / Shafer, C.M. / Harrison, S.D. / Johnson, K.W. / Bussiere, D.E.
History
DepositionOct 8, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glycogen synthase kinase-3 beta
C: VAL-SEP-ARG-ARG
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0374
Polymers47,4802
Non-polymers5572
Water3,657203
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area810 Å2
ΔGint-9 kcal/mol
Surface area16660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.747, 65.070, 57.336
Angle α, β, γ (deg.)90.00, 100.53, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 46881.195 Da / Num. of mol.: 1
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: Protein/peptide VAL-SEP-ARG-ARG


Mass: 598.590 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-65C / CHIR99021 / 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile


Mass: 465.338 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18Cl2N8 / Comment: inhibitor*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.19 Å3/Da / Density % sol: 43.89 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / Details: 7-12% (w:v) PEG 6000 and 5-8% MPD (v:v)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jan 15, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.595→25 Å / Num. obs: 12763 / % possible obs: 99.7 % / Redundancy: 4.6 % / Net I/σ(I): 12.4

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Processing

Software
NameClassification
PHENIXrefinement
DENZOdata reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.595→25 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.2466 --
Rwork0.2121 --
obs0.2155 12125 99.7 %
Refinement stepCycle: LAST / Resolution: 2.595→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2766 0 38 203 3007
LS refinement shellResolution: 2.595→2.698 Å / Rfactor Rfree: 0.3037 / Rfactor Rwork: 0.2605

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