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- PDB-5f95: Crystal structure of GSK3b in complex with Compound 18: 2-[(cyclo... -

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Basic information

Entry
Database: PDB / ID: 5f95
TitleCrystal structure of GSK3b in complex with Compound 18: 2-[(cyclopropylcarbonyl)amino]-N-(4-phenylpyridin-3-yl)pyridine-4-carboxamide
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / GSK3b / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 cilium assembly / beta-catenin destruction complex / CRMPs in Sema3A signaling / heart valve development / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / tau-protein kinase / regulation of microtubule-based process / regulation of protein export from nucleus / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 long-term synaptic potentiation / 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 / tau-protein kinase activity / negative regulation of epithelial to mesenchymal transition / G protein-coupled dopamine receptor signaling pathway / positive regulation of cell-matrix adhesion / regulation of axonogenesis / regulation of dendrite morphogenesis / glycogen metabolic process / ER overload response / regulation of neuron projection development / establishment of cell polarity / protein kinase A catalytic subunit binding / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / NF-kappaB binding / canonical Wnt signaling pathway / 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 / cellular response to retinoic acid / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of autophagy / Transcriptional and post-translational regulation of MITF-M expression and activity / presynaptic modulation of chemical synaptic transmission / 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 / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H2AS121 kinase activity / histone H3S57 kinase activity / excitatory postsynaptic potential / histone H3S28 kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / ribosomal protein S6 kinase activity / histone H2AT120 kinase activity / eukaryotic translation initiation factor 2alpha kinase activity / histone H2BS36 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3S10 kinase activity / AMP-activated protein kinase activity / histone H3T11 kinase activity / histone H3T3 kinase activity / 3-phosphoinositide-dependent protein kinase activity / Ubiquitin-dependent degradation of Cyclin D / histone H3T45 kinase activity / mitochondrion organization / positive regulation of cell differentiation / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / positive regulation of protein-containing complex assembly / negative regulation of canonical Wnt signaling pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2
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-3UP / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.525 Å
AuthorsLewis, H.A. / Kish, K. / Luo, G. / Dubowchick, G.M.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors.
Authors: Luo, G. / Chen, L. / Burton, C.R. / Xiao, H. / Sivaprakasam, P. / Krause, C.M. / Cao, Y. / Liu, N. / Lippy, J. / Clarke, W.J. / Snow, K. / Raybon, J. / Arora, V. / Pokross, M. / Kish, K. / ...Authors: Luo, G. / Chen, L. / Burton, C.R. / Xiao, H. / Sivaprakasam, P. / Krause, C.M. / Cao, Y. / Liu, N. / Lippy, J. / Clarke, W.J. / Snow, K. / Raybon, J. / Arora, V. / Pokross, M. / Kish, K. / Lewis, H.A. / Langley, D.R. / Macor, J.E. / Dubowchik, G.M.
History
DepositionDec 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2016Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)80,4044
Polymers79,6882
Non-polymers7172
Water1,24369
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2022
Polymers39,8441
Non-polymers3581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2022
Polymers39,8441
Non-polymers3581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)80.979, 82.744, 177.609
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 39843.848 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: unidentified baculovirus
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-3UP / 2-[(cyclopropylcarbonyl)amino]-N-(4-phenylpyridin-3-yl)pyridine-4-carboxamide


Mass: 358.393 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.76 Å3/Da / Density % sol: 67.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: Crystals grown in the presence of 25% PEG 1500 and 0.1 M MMT pH 4.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→30.3 Å / Num. obs: 40511 / % possible obs: 99.8 % / Redundancy: 5.9 % / Net I/σ(I): 10.4

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementResolution: 2.525→30.274 Å / SU ML: 0.37 / Cross valid method: FREE R-VALUE / σ(F): 1.9 / Phase error: 28.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2424 2023 5.01 %
Rwork0.2015 --
obs0.2036 40371 98.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.525→30.274 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5047 0 54 69 5170
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095234
X-RAY DIFFRACTIONf_angle_d1.197182
X-RAY DIFFRACTIONf_dihedral_angle_d12.4451848
X-RAY DIFFRACTIONf_chiral_restr0.049830
X-RAY DIFFRACTIONf_plane_restr0.007978
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.525-2.58810.37011160.31762387X-RAY DIFFRACTION88
2.5881-2.6580.38371320.31072707X-RAY DIFFRACTION99
2.658-2.73620.37351480.28732702X-RAY DIFFRACTION99
2.7362-2.82440.32041540.26012740X-RAY DIFFRACTION100
2.8244-2.92530.33011570.25312701X-RAY DIFFRACTION100
2.9253-3.04230.34371490.24522741X-RAY DIFFRACTION100
3.0423-3.18060.28041180.24112753X-RAY DIFFRACTION99
3.1806-3.34810.32451350.22342754X-RAY DIFFRACTION100
3.3481-3.55760.2561560.21442757X-RAY DIFFRACTION100
3.5576-3.83180.21231390.18672765X-RAY DIFFRACTION100
3.8318-4.21650.19271550.16922765X-RAY DIFFRACTION100
4.2165-4.82450.1861460.14482805X-RAY DIFFRACTION100
4.8245-6.07030.22141630.18652816X-RAY DIFFRACTION100
6.0703-30.27640.20081550.18562955X-RAY DIFFRACTION100
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)
11.3583-1.21010.05711.0802-0.11991.28420.012-0.04410.0611-0.0087-0.0566-0.10760.13140.0193-0.00110.4645-0.04810.00280.2781-0.02450.4504-0.9624-6.1554-37.1596
20.71750.16930.03240.42630.09510.9433-0.0121-0.0065-0.01160.1090.0040.15570.0894-0.4100.4503-0.05660.02460.3888-0.0130.3876-20.54621.355-37.7228
35.04630.23253.59223.36720.56693.01730.4775-0.3471-0.55141.24510.34410.5331-0.1008-0.71370.79050.6561-0.06290.1950.86960.03740.6245-40.08064.2976-31.4477
40.02050.0067-0.14891.0706-0.20361.8149-0.03810.31720.0591-0.29060.094-0.023-0.2547-0.32390.00010.488-0.0012-0.04450.4889-0.03650.4328-21.29767.0693-52.3756
51.1088-0.0621-0.84490.8180.24633.899-0.07810.14780.25280.14830.36530.0912-0.26680.2054-0.26690.25840.07460.05170.3988-0.02990.4333-33.574826.5479-8.3784
60.4525-0.269-0.47651.67021.07111.7642-0.23140.2165-0.0831-0.05110.38150.3247-0.239-0.6313-0.01410.3881-0.02610.01050.71750.06240.4467-38.737316.8206-9.2383
70.842-0.5451-0.46531.53430.54441.56180.0091-0.13610.03620.0478-0.1614-0.16370.13210.0162-0.0020.3404-0.11650.03540.42980.00470.3429-20.141710.4834-3.4276
80.6614-0.5423-0.54041.0967-0.52871.84760.09270.0593-0.12290.1005-0.11640.07730.4583-0.47270.00030.4052-0.07110.01840.4757-0.0210.4049-26.00921.8515-10.6325
91.3706-1.09721.15142.1265-1.12181.03870.08690.62170.0009-0.5893-0.1534-0.05070.09270.7960.04480.50240.03450.0640.3881-0.04340.4402-13.6916-5.1453-18.4174
101.1636-0.358-1.47140.42620.60551.9342-0.5371-0.4494-0.02380.06930.15160.2810.64430.3079-0.11020.72090.06760.03730.29360.06850.6896-15.0874-12.5967-10.8648
111.2632-0.00610.42271.0486-0.8391.25340.1744-0.4201-0.09150.3078-0.1145-0.19680.2505-0.20580.00210.6007-0.10920.01210.5890.03070.4785-21.3944-1.0857.365
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 36:154 )A36 - 154
2X-RAY DIFFRACTION2( CHAIN A AND RESID 155:273 )A155 - 273
3X-RAY DIFFRACTION3( CHAIN A AND RESID 274:300 )A274 - 300
4X-RAY DIFFRACTION4( CHAIN A AND RESID 301:383 )A301 - 383
5X-RAY DIFFRACTION5( CHAIN B AND RESID 36:88 )B36 - 88
6X-RAY DIFFRACTION6( CHAIN B AND RESID 89:126 )B89 - 126
7X-RAY DIFFRACTION7( CHAIN B AND RESID 127:175 )B127 - 175
8X-RAY DIFFRACTION8( CHAIN B AND RESID 176:252 )B176 - 252
9X-RAY DIFFRACTION9( CHAIN B AND RESID 253:273 )B253 - 273
10X-RAY DIFFRACTION10( CHAIN B AND RESID 274:310 )B274 - 310
11X-RAY DIFFRACTION11( CHAIN B AND RESID 311:385 )B311 - 385

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