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- PDB-6hk3: Crystal structure of GSK-3B in complex with pyrazine inhibitor C44 -

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Basic information

Entry
Database: PDB / ID: 6hk3
TitleCrystal structure of GSK-3B in complex with pyrazine inhibitor C44
Components
  • GLY-SER-HIS-GLY-HIS-HIS-HIS-HIS
  • Glycogen synthase kinase-3 beta
KeywordsTRANSFERASE / GSK 3B / Complex / pyrazine / inhibitor
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 / beta-catenin destruction complex disassembly / 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 dopaminergic neuron differentiation ...negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of mesenchymal stem cell differentiation / beta-catenin destruction complex disassembly / 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 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 / 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 / regulation of microtubule-based process / CRMPs in Sema3A signaling / regulation of protein export from nucleus / heart valve development / 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 / Wnt signalosome / regulation of axon extension / regulation of long-term synaptic potentiation / negative regulation of protein localization to nucleus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / positive regulation of cell-matrix adhesion / negative regulation of calcineurin-NFAT signaling cascade / dopamine receptor signaling pathway / regulation of dendrite morphogenesis / negative regulation of phosphoprotein phosphatase activity / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / protein kinase A catalytic subunit binding / NF-kappaB binding / canonical Wnt signaling pathway / Regulation of HSF1-mediated heat shock response / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / excitatory postsynaptic potential / presynaptic modulation of chemical synaptic transmission / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / hippocampus development / positive regulation of protein-containing complex assembly / positive regulation of cell differentiation / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / peptidyl-threonine phosphorylation / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / 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 / regulation of circadian rhythm / beta-catenin binding / positive regulation of GTPase activity / circadian rhythm / positive regulation of protein catabolic process / cellular response to amyloid-beta / neuron projection development / Regulation of RUNX2 expression and activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / insulin receptor signaling pathway / positive regulation of protein binding / kinase activity / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / peptidyl-serine phosphorylation
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 ...Glycogen synthase kinase 3, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-G8B / MALONATE ION / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Glycogen synthase kinase-3 beta
B: Glycogen synthase kinase-3 beta
N: GLY-SER-HIS-GLY-HIS-HIS-HIS-HIS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,44015
Polymers80,6753
Non-polymers1,76512
Water3,387188
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8578
Polymers39,8831
Non-polymers9747
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area960 Å2
ΔGint-6 kcal/mol
Surface area16630 Å2
MethodPISA
2
B: Glycogen synthase kinase-3 beta
hetero molecules

N: GLY-SER-HIS-GLY-HIS-HIS-HIS-HIS


Theoretical massNumber of molelcules
Total (without water)41,5837
Polymers40,7932
Non-polymers7905
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_655x+1,y,z1
Buried area1680 Å2
ΔGint-9 kcal/mol
Surface area17170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.318, 67.117, 67.238
Angle α, β, γ (deg.)79.840, 76.210, 89.630
Int Tables number1
Space group name H-MP1

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Components

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Protein / Protein/peptide , 2 types, 3 molecules ABN

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


Mass: 39882.773 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
#2: Protein/peptide GLY-SER-HIS-GLY-HIS-HIS-HIS-HIS


Mass: 909.931 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)

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Non-polymers , 6 types, 200 molecules

#3: Chemical ChemComp-G8B / 3-azanyl-~{N}-(2-methoxyphenyl)-6-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]pyrazine-2-carboxamide


Mass: 482.555 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N6O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MLI / MALONATE ION / Malonic acid


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


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 3.44 Å3/Da / Density % sol: 64.21 %
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: Mar 20, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→46.22 Å / Num. obs: 46585 / % possible obs: 97.1 % / Redundancy: 2.4 % / CC1/2: 0.994 / Rmerge(I) obs: 0.098 / Rpim(I) all: 0.077 / Rrim(I) all: 0.125 / Net I/σ(I): 5.2 / Num. measured all: 113743 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.3-2.382.51.4541052342280.3411.1171.8440.589.5
8.89-46.222.60.03820778140.9950.0290.04818.798.2

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Processing

Software
NameVersionClassification
REFMACrefinement
Aimless0.6.2data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ACD

4acd


Resolution: 2.35→42.977 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 26.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2335 2182 4.99 %
Rwork0.2041 --
obs0.2056 43734 97.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 136.69 Å2 / Biso mean: 56.4885 Å2 / Biso min: 18.99 Å2
Refinement stepCycle: final / Resolution: 2.35→42.977 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5572 0 116 192 5880
Biso mean--49.89 55.1 -
Num. residues----708

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