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- PDB-6h0u: Glycogen synthase kinase-3 beta (GSK3) complex with a covalent [1... -

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Basic information

Entry
Database: PDB / ID: 6h0u
TitleGlycogen synthase kinase-3 beta (GSK3) complex with a covalent [1,2,4]triazolo[1,5-a][1,3,5]triazine inhibitor
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / Protein Kinase / GSK3beta-Covalent Inhibitor Complex / Parkinson Disease
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 mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of cilium assembly / 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 / CRMPs in Sema3A signaling / heart valve development / 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 / Maturation of nucleoprotein / cellular response to interleukin-3 / regulation of long-term synaptic potentiation / Wnt signalosome / 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 / G protein-coupled dopamine receptor signaling pathway / negative regulation of epithelial to mesenchymal transition / tau-protein kinase activity / positive regulation of cell-matrix adhesion / regulation of axonogenesis / regulation of dendrite morphogenesis / ER overload response / glycogen metabolic process / regulation of neuron projection development / establishment of cell polarity / protein kinase A catalytic subunit binding / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / epithelial to mesenchymal transition / canonical Wnt signaling pathway / NF-kappaB 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 in absence of ligand / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / 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 / response to endoplasmic reticulum stress / negative regulation of cell migration / hippocampus development / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / excitatory postsynaptic potential / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / 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 / regulation of circadian rhythm / beta-catenin binding / Degradation of beta-catenin by the destruction complex / B-WICH complex positively regulates rRNA expression / tau protein binding / Wnt signaling pathway / circadian rhythm / cellular response to amyloid-beta / positive regulation of protein catabolic process / neuron projection development / Regulation of RUNX2 expression and activity / kinase activity / positive regulation of protein binding / p53 binding / positive regulation of neuron apoptotic process / insulin receptor signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / presynapse
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-FKB / MALONATE ION / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMarcovich, I. / Demitri, N. / De Zorzi, R. / Storici, P.
CitationJournal: Chemmedchem / Year: 2019
Title: A Triazolotriazine-Based Dual GSK-3 beta /CK-1 delta Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition.
Authors: Redenti, S. / Marcovich, I. / De Vita, T. / Perez, C. / De Zorzi, R. / Demitri, N. / Perez, D.I. / Bottegoni, G. / Bisignano, P. / Bissaro, M. / Moro, S. / Martinez, A. / Storici, P. / ...Authors: Redenti, S. / Marcovich, I. / De Vita, T. / Perez, C. / De Zorzi, R. / Demitri, N. / Perez, D.I. / Bottegoni, G. / Bisignano, P. / Bissaro, M. / Moro, S. / Martinez, A. / Storici, P. / Spalluto, G. / Cavalli, A. / Federico, S.
History
DepositionJul 10, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)94,73311
Polymers93,6022
Non-polymers1,1319
Water4,792266
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.803, 94.542, 106.579
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: ARG / End label comp-ID: ARG / Refine code: 5 / Auth seq-ID: 36 - 383 / Label seq-ID: 36 - 383

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.099045, 0.599151, 0.794486), (0.639686, -0.573242, 0.512049), (0.762228, 0.558938, -0.326492)36.85856, -68.10525, 11.53673

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 46801.215 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

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Non-polymers , 6 types, 275 molecules

#2: Chemical ChemComp-FKB / (2~{R})-3-[7-azanyl-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl]-2-cyano-propanamide


Mass: 329.360 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H19N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H2O4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / Source method: isolated from a natural source / Formula: H2O

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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: 2.65 Å3/Da / Density % sol: 53.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: GSK3beta(35-386) aliquots were concentrated to 4.4 mg/ml and used for crystallization trials. GSK3b-inhibitor co-crystals were grown using the sitting drop vapor diffusion technique in 0.2M ...Details: GSK3beta(35-386) aliquots were concentrated to 4.4 mg/ml and used for crystallization trials. GSK3b-inhibitor co-crystals were grown using the sitting drop vapor diffusion technique in 0.2M DL-Malic acid pH 7.0, 20% PEG 3350 as reservoir solution. The protein was previously incubated with 3x molar excess of compound for 3h at 4C. Crystallization drops were prepared from 0.5ul of protein solution and 0.5ul of reservoir, and incubated for 10 days at 20C. Crystals were cryoprotected in 30% Glycerol and frozen in liquid nitrogen prior to data collection.

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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: Jan 31, 2018
RadiationMonochromator: Si111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→47.27 Å / Num. obs: 39567 / % possible obs: 99.8 % / Redundancy: 3.7 % / CC1/2: 0.991 / Rpim(I) all: 0.084 / Χ2: 1.05 / Net I/σ(I): 7.4
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.8 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3843 / CC1/2: 0.57 / Rpim(I) all: 0.72 / Χ2: 1.01 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Q5K

1q5k


Resolution: 2.3→47.27 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.926 / SU B: 8.157 / SU ML: 0.187 / Cross valid method: THROUGHOUT / ESU R: 0.295 / ESU R Free: 0.224 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24047 1969 5 %RANDOM
Rwork0.19236 ---
obs0.19483 37543 99.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 37.707 Å2
Baniso -1Baniso -2Baniso -3
1--1.1 Å2-0 Å20 Å2
2--1.14 Å2-0 Å2
3----0.04 Å2
Refinement stepCycle: 1 / Resolution: 2.3→47.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5580 0 76 266 5922
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0145793
X-RAY DIFFRACTIONr_bond_other_d0.0020.0175252
X-RAY DIFFRACTIONr_angle_refined_deg1.3861.6817872
X-RAY DIFFRACTIONr_angle_other_deg0.9941.64212339
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5225690
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.16321.06302
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.52215964
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2771546
X-RAY DIFFRACTIONr_chiral_restr0.0660.2753
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026384
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021044
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_it2.8073.6922778
X-RAY DIFFRACTIONr_mcbond_other2.8073.6912777
X-RAY DIFFRACTIONr_mcangle_it4.5495.5343462
X-RAY DIFFRACTIONr_mcangle_other4.5485.5363463
X-RAY DIFFRACTIONr_scbond_it3.1574.1053015
X-RAY DIFFRACTIONr_scbond_other3.1574.1053015
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.0985.9694411
X-RAY DIFFRACTIONr_long_range_B_refined7.99642.3186441
X-RAY DIFFRACTIONr_long_range_B_other7.99342.3156419
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Auth asym-IDNumberTypeRms dev position (Å)Weight position
A2043medium positional0.270.5
A3387loose positional0.575
B2043medium thermal5.842
B3387loose thermal6.3210
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.401 149 -
Rwork0.343 2729 -
obs--99.93 %

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