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- PDB-6y9s: Crystal structure of GSK-3b in complex with the imidazo[1,5-a]pyr... -

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Basic information

Entry
Database: PDB / ID: 6y9s
TitleCrystal structure of GSK-3b in complex with the imidazo[1,5-a]pyridine-3-carboxamide inhibitor 16
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / GLYCOGEN SYNTHASE KINASE-3 BETA / INDAZOLE / INHIBITOR / KINASE / PROTEROS BIOSTRUCTURES GMBH
Function / homology
Function and homology information


regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / 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 ...regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / 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 / 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 / Wnt signalosome / negative regulation of protein localization to nucleus / negative regulation of TOR signaling / 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 calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / dopamine receptor signaling pathway / negative regulation of phosphoprotein phosphatase activity / regulation of dendrite morphogenesis / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / glycogen metabolic process / ER overload response / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / NF-kappaB binding / Regulation of HSF1-mediated heat shock response / epithelial to mesenchymal transition / canonical Wnt signaling pathway / 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 / presynaptic modulation of chemical synaptic transmission / excitatory postsynaptic potential / negative regulation of insulin receptor signaling pathway / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / hippocampus development / 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 / positive regulation of protein-containing complex assembly / Degradation of beta-catenin by the destruction complex / tau protein binding / negative regulation of canonical Wnt signaling pathway / 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 / Regulation of RUNX2 expression and activity / neuron projection development / positive regulation of neuron apoptotic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / positive regulation of protein binding / insulin receptor signaling pathway / negative regulation of neuron projection development / 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
ACETATE ION / Chem-OHK / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsKrapp, S. / Griessner, A. / Blaesse, M. / Buonfiglio, R. / Ombrato, R.
CitationJournal: Molecules / Year: 2020
Title: Discovery of Novel Imidazopyridine GSK-3 beta Inhibitors Supported by Computational Approaches.
Authors: Buonfiglio, R. / Prati, F. / Bischetti, M. / Cavarischia, C. / Furlotti, G. / Ombrato, R.
History
DepositionMar 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 20, 2020Provider: repository / Type: Initial release

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Structure visualization

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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)80,7327
Polymers79,7662
Non-polymers9665
Water5,080282
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3954
Polymers39,8831
Non-polymers5133
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3363
Polymers39,8831
Non-polymers4542
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.109, 96.185, 67.560
Angle α, β, γ (deg.)90.000, 103.590, 90.000
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: 39882.773 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
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-OHK / ~{N}-(oxan-4-ylmethyl)-6-(5-propan-2-yloxypyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide


Mass: 394.467 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 282 / 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: 2.7 Å3/Da / Density % sol: 54.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.10 M TrisAc pH8.25 26 % PEG 8K 0.13 M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 23, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 2.03→65.67 Å / Num. obs: 50808 / % possible obs: 94.2 % / Redundancy: 2 % / Biso Wilson estimate: 41.797 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.055 / Rrim(I) all: 0.074 / Χ2: 0.974 / Net I/σ(I): 9.63
Reflection shellResolution: 2.03→2.28 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.448 / Mean I/σ(I) obs: 1.78 / Num. unique obs: 14391 / CC1/2: 0.771 / Rrim(I) all: 0.028 / % possible all: 91.4

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.03→65.67 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.938 / SU B: 6.563 / SU ML: 0.164 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.199 / ESU R Free: 0.179
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2493 1682 3.3 %RANDOM
Rwork0.2025 ---
obs0.204 49126 94.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 170.44 Å2 / Biso mean: 41.632 Å2 / Biso min: 19 Å2
Baniso -1Baniso -2Baniso -3
1--1.02 Å2-0 Å2-1.3 Å2
2--0.07 Å20 Å2
3---1.42 Å2
Refinement stepCycle: final / Resolution: 2.03→65.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5472 0 70 282 5824
Biso mean--36.83 40.14 -
Num. residues----684
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0195612
X-RAY DIFFRACTIONr_bond_other_d0.0030.025335
X-RAY DIFFRACTIONr_angle_refined_deg1.5111.9947661
X-RAY DIFFRACTIONr_angle_other_deg1.201312248
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4135686
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.62523.362235
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.25815880
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0431538
X-RAY DIFFRACTIONr_chiral_restr0.0820.2866
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0216304
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021270
LS refinement shellResolution: 2.03→2.083 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 85 -
Rwork0.373 3007 -
all-3092 -
obs--78.42 %

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