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- PDB-6y9r: Crystal structure of GSK-3b in complex with the 1H-indazole-3-car... -

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Basic information

Entry
Database: PDB / ID: 6y9r
TitleCrystal structure of GSK-3b in complex with the 1H-indazole-3-carboxamide inhibitor 2
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-OH8 / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 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
Revision 1.1Jul 8, 2020Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rmerge_I_obs / _reflns_shell.Rmerge_I_obs

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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)40,5785
Polymers39,8831
Non-polymers6954
Water2,396133
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area650 Å2
ΔGint1 kcal/mol
Surface area17450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.581, 108.291, 103.474
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 39882.773 Da / Num. of mol.: 1 / 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-OH8 / ~{N}-[[1-(2-methoxyethyl)piperidin-4-yl]methyl]-5-(5-propan-2-yloxypyridin-3-yl)-1~{H}-indazole-3-carboxamide


Mass: 451.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 3.01 Å3/Da / Density % sol: 59.14 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 18 % PEG8000 0.13 M NaCl 0.10 M Tris_Acetat_7.5 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 2.08→66.66 Å / Num. obs: 28265 / % possible obs: 97.8 % / Redundancy: 5.2 % / Biso Wilson estimate: 46.432 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.055 / Rrim(I) all: 0.061 / Χ2: 1.026 / Net I/σ(I): 16.89 / Num. measured all: 146081 / Scaling rejects: 87
Reflection shellResolution: 2.08→66.66 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.435 / Mean I/σ(I) obs: 48.2 / Num. measured obs: 445 / Num. possible: 122 / Num. unique obs: 104 / CC1/2: 0.999 / Rrim(I) all: 0.022 / % possible all: 97.2

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.08→66.66 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.938 / SU B: 11.974 / SU ML: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.184 / ESU R Free: 0.162
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2261 1671 5.9 %RANDOM
Rwork0.1891 ---
obs0.1914 26594 97.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 135.79 Å2 / Biso mean: 53.315 Å2 / Biso min: 25.55 Å2
Baniso -1Baniso -2Baniso -3
1--3.8 Å2-0 Å20 Å2
2---1.45 Å20 Å2
3---5.25 Å2
Refinement stepCycle: final / Resolution: 2.08→66.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2808 0 47 133 2988
Biso mean--53.4 47.75 -
Num. residues----350
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192948
X-RAY DIFFRACTIONr_bond_other_d0.0010.022796
X-RAY DIFFRACTIONr_angle_refined_deg1.3681.9944031
X-RAY DIFFRACTIONr_angle_other_deg2.52536422
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0355363
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.63223.175126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.90515464
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8391522
X-RAY DIFFRACTIONr_chiral_restr0.0730.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213332
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02678
LS refinement shellResolution: 2.08→2.134 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 133 -
Rwork0.318 1819 -
all-1952 -
obs--92.95 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.0083-0.704-1.76342.17260.75485.41810.15860.4259-0.1911-0.1471-0.1739-0.1187-0.0390.19080.01520.24460.0866-0.02540.1003-0.02610.2373-2.154-21.019-4.998
23.61630.56830.24992.56590.26812.2047-0.0098-0.3096-0.17080.1546-0.0270.1351-0.0316-0.1050.03680.1855-0.0132-0.01160.0320.01940.0561-18.58-11.65215.636
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 135
2X-RAY DIFFRACTION2A136 - 400

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