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- PDB-6hk7: Crystal structure of GSK-3B in complex with pyrazine inhibitor C50 -

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Basic information

Entry
Database: PDB / ID: 6hk7
TitleCrystal structure of GSK-3B in complex with pyrazine inhibitor C50
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / GSK 3B / Complex / pyrazine / inhibitor
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 / CRMPs in Sema3A signaling / heart valve development / 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 / 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 / cellular response to interleukin-3 / Maturation of nucleoprotein / Wnt signalosome / regulation of long-term synaptic potentiation / negative regulation of TOR signaling / negative regulation of protein localization to nucleus / regulation of microtubule-based process / AKT phosphorylates targets in the cytosol / Disassembly of the destruction complex and recruitment of AXIN to the membrane / 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 / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / establishment of cell polarity / protein kinase A catalytic subunit binding / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / canonical Wnt signaling pathway / NF-kappaB binding / negative regulation of osteoblast differentiation / 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 / 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 / negative regulation of cell migration / response to endoplasmic reticulum stress / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / mitochondrion organization / excitatory postsynaptic potential / hippocampus development / positive regulation of cell differentiation / positive regulation of protein-containing complex assembly / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / negative regulation of canonical Wnt signaling pathway / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / circadian rhythm / regulation of circadian rhythm / Degradation of beta-catenin by the destruction complex / beta-catenin binding / peptidyl-serine phosphorylation / B-WICH complex positively regulates rRNA expression / tau protein binding / Wnt signaling pathway / cellular response to amyloid-beta / neuron projection development / Regulation of RUNX2 expression and activity / positive regulation of protein catabolic process / p53 binding / kinase activity / insulin receptor signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of neuron apoptotic process
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
Chem-G8N / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsPiretti, V. / Giabbai, B. / Demitri, N. / Di Martino, R. / Tripathi, S.K. / Gobbo, D. / Decherchi, S. / Storici, P. / Girotto, S. / Cavalli, A.
CitationJournal: J Chem Theory Comput / Year: 2019
Title: Investigating Drug-Target Residence Time in Kinases through Enhanced Sampling Simulations.
Authors: Gobbo, D. / Piretti, V. / Di Martino, R.M.C. / Tripathi, S.K. / Giabbai, B. / Storici, P. / Demitri, N. / Girotto, S. / Decherchi, S. / Cavalli, A.
History
DepositionSep 5, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 17, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,1304
Polymers39,5251
Non-polymers6053
Water181
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area540 Å2
ΔGint3 kcal/mol
Surface area16550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.979, 103.727, 108.920
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 39525.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-G8N / 3-azanyl-~{N}-(2-methoxyethyl)-6-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]pyrazine-2-carboxamide


Mass: 434.513 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H26N6O4S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 3.07 Å3/Da / Density % sol: 59.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: 0.2M potassium fluoride 22% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 5.2R / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→51.86 Å / Num. obs: 10015 / % possible obs: 99.5 % / Redundancy: 5.4 % / CC1/2: 0.973 / Rmerge(I) obs: 0.281 / Rpim(I) all: 0.133 / Rrim(I) all: 0.312 / Net I/σ(I): 4.9 / Num. measured all: 53759 / Scaling rejects: 19
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
3-3.185.71.06115850.750.4781.16698.8
9.01-51.865.40.1034190.9850.0490.11598.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
Aimless0.7.2data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ACD

4acd


Resolution: 3.2→46.87 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.853 / SU B: 65.595 / SU ML: 0.481 / Cross valid method: THROUGHOUT / ESU R Free: 0.541 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28552 412 5 %RANDOM
Rwork0.20004 ---
obs0.20436 7856 99.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 47.85 Å2
Baniso -1Baniso -2Baniso -3
1--6.28 Å2-0 Å20 Å2
2--1.57 Å2-0 Å2
3---4.7 Å2
Refinement stepCycle: 1 / Resolution: 3.2→46.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2615 0 40 1 2656
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0142721
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172347
X-RAY DIFFRACTIONr_angle_refined_deg1.7171.6893723
X-RAY DIFFRACTIONr_angle_other_deg1.0621.6585472
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5155346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.70321.667120
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.57415382
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.751515
X-RAY DIFFRACTIONr_chiral_restr0.0850.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023080
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02508
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it10.0775.1631387
X-RAY DIFFRACTIONr_mcbond_other10.0685.1621386
X-RAY DIFFRACTIONr_mcangle_it13.9057.7671732
X-RAY DIFFRACTIONr_mcangle_other13.9027.7691733
X-RAY DIFFRACTIONr_scbond_it9.425.2491334
X-RAY DIFFRACTIONr_scbond_other9.4175.2471335
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other12.627.8071992
X-RAY DIFFRACTIONr_long_range_B_refined17.4985956
X-RAY DIFFRACTIONr_long_range_B_other17.4975957
X-RAY DIFFRACTIONr_rigid_bond_restr10.93335068
X-RAY DIFFRACTIONr_sphericity_free41.66352
X-RAY DIFFRACTIONr_sphericity_bonded60.45955001
LS refinement shellResolution: 3.2→3.283 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 27 -
Rwork0.28 554 -
obs--99.83 %

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