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- PDB-7z1f: Crystal structure of GSK3b in complex with CX-4945 -

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Basic information

Entry
Database: PDB / ID: 7z1f
TitleCrystal structure of GSK3b in complex with CX-4945
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / Kinase / diabetes / kinase inhibitor
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 / G protein-coupled dopamine receptor signaling pathway / negative regulation of phosphoprotein phosphatase activity / regulation of dendrite morphogenesis / establishment of cell polarity / regulation of axonogenesis / 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 / negative regulation of osteoblast differentiation / canonical Wnt signaling pathway / 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 / negative regulation of insulin receptor signaling pathway / excitatory postsynaptic potential / positive regulation of protein export from nucleus / positive regulation of GTPase activity / 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 / negative regulation of canonical Wnt signaling pathway / tau protein binding / B-WICH complex positively regulates rRNA expression / regulation of circadian rhythm / beta-catenin binding / 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 / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 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
Chem-3NG / IMIDAZOLE / YTTRIUM (III) ION / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsGrygier, P. / Pustelny, K. / Dubin, G. / Czarna, A.
Funding support Poland, 2items
OrganizationGrant numberCountry
Polish National Science Centre2019/34/E/NZ1/00467 Poland
National Center for Research and Development (Poland)PPN/PPO/2018/1/00046 Poland
CitationJournal: To Be Published
Title: Crystal structure of phosphorylated (Tyr216) GSK3b kinase in complex with CX-4945
Authors: Grygier, P. / Pustelny, K. / Golik, P. / Popowicz, G. / Dubin, G. / Czarna, A.
History
DepositionFeb 24, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)84,2949
Polymers83,1692
Non-polymers1,1247
Water95553
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1815
Polymers41,5851
Non-polymers5974
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1124
Polymers41,5851
Non-polymers5283
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.001, 86.001, 237.735
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 41584.648 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Escherichia coli (E. coli) / Strain (production host): LOBSTR
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-3NG / 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid


Mass: 349.770 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H12ClN3O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: chemotherapy, inhibitor*YM
#3: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#4: Chemical
ChemComp-YT3 / YTTRIUM (III) ION


Mass: 88.906 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Y
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 3.05 Å3/Da / Density % sol: 59.69 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 1.0 M Sodium acetate trihydrate 0.1 M Imidazole pH 6.5, 10 mM Yttrium (III) chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.885603 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Sep 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.885603 Å / Relative weight: 1
ReflectionResolution: 3→46.46 Å / Num. obs: 21174 / % possible obs: 99.9 % / Redundancy: 6.2 % / Biso Wilson estimate: 77.31 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.201 / Rpim(I) all: 0.087 / Rrim(I) all: 0.22 / Net I/σ(I): 6 / Num. measured all: 130705 / Scaling rejects: 71
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
3-3.186.41.4342141633680.6040.6141.5631.599.9
9-46.465.50.11947518670.9850.0520.1313.397.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimless0.7.7data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GN1

6gn1


Resolution: 3→46.46 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2487 1109 5.25 %RANDOM
Rwork0.2227 20025 --
obs0.224 21134 99.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 201.92 Å2 / Biso mean: 84.9592 Å2 / Biso min: 36.18 Å2
Refinement stepCycle: final / Resolution: 3→46.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5097 0 59 53 5209
Biso mean--84.16 76.27 -
Num. residues----678
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3-3.140.3811350.321224422577100
3.14-3.30.34131290.302324922621100
3.3-3.510.25831490.256124302579100
3.51-3.780.22631220.218324972619100
3.78-4.160.26231430.219424642607100
4.16-4.760.19511370.177325282665100
4.76-60.24191600.220525142674100
6-46.460.24721340.21332658279299
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)
18.7134-1.59044.26222.1327-0.4314.90710.06270.9180.405-0.7909-0.2057-0.1271-0.13580.32010.22450.859-0.06220.01980.81960.33290.895231.6074-3.3925-6.8357
25.2023-1.3076-0.39878.7638-2.97754.99360.07720.39790.5236-0.02740.09850.3059-0.60590.1231-0.16150.5553-0.1729-0.03280.59560.06150.480429.6855-9.39722.8429
32.416-0.02560.94954.63331.57116.92850.1524-0.22330.27350.2843-0.3350.303-0.1162-0.19440.17380.3595-0.1339-0.03680.57140.00220.46931.3248-24.315520.0344
46.0712-3.2995-2.67424.6499-0.34176.9074-0.2102-1.03210.16081.50320.2638-0.65431.10930.7630.01870.9855-0.1597-0.10990.98140.04780.563335.4732-27.391239.9677
51.3984-0.8523-0.38116.01891.28268.55540.2504-0.2347-0.36160.6762-0.1698-0.45321.13960.6021-0.05220.5495-0.0655-0.09990.48150.12630.550938.4565-35.819222.0888
65.51452.14172.5667.8595-0.34728.10110.04760.9081-0.883-0.28030.0762-1.15930.82591.6954-0.14560.56570.13140.0260.8682-0.0380.625945.4554-34.68565.8598
71.5854-1.26-1.30742.76840.9211.1515-1.5675-0.04751.40250.0940.05010.1146-1.6382-0.63790.79871.7750.2366-0.95891.0392-0.16091.446477.1466-2.273427.5165
87.6388-0.21235.54772.878-0.18317.1508-0.1826-0.1876-0.1385-0.03860.18190.2083-0.383-0.13080.00410.48080.01410.00830.62450.03550.4277.091-26.899120.511
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 28 through 51 )A28 - 51
2X-RAY DIFFRACTION2chain 'A' and (resid 52 through 138 )A52 - 138
3X-RAY DIFFRACTION3chain 'A' and (resid 139 through 273 )A139 - 273
4X-RAY DIFFRACTION4chain 'A' and (resid 274 through 304 )A274 - 304
5X-RAY DIFFRACTION5chain 'A' and (resid 305 through 344 )A305 - 344
6X-RAY DIFFRACTION6chain 'A' and (resid 345 through 386 )A345 - 386
7X-RAY DIFFRACTION7chain 'B' and (resid 38 through 138 )B38 - 138
8X-RAY DIFFRACTION8chain 'B' and (resid 139 through 382 )B139 - 382

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