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- PDB-5k5n: Crystal structure of GSK-3beta complexed with PF-04802367, a high... -

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Basic information

Entry
Database: PDB / ID: 5k5n
TitleCrystal structure of GSK-3beta complexed with PF-04802367, a highly selective brain-penetrant kinase inhibitor
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / Protein kinase / Alzhimer's disease / tau kinase
Function / homology
Function and homology information


regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium ...regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of dopaminergic neuron differentiation / positive regulation of protein localization to centrosome / maintenance of cell polarity / 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 / negative regulation of TOR signaling / Wnt signalosome / negative regulation of protein localization to nucleus / 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 epithelial to mesenchymal transition / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / G protein-coupled dopamine receptor signaling pathway / regulation of axonogenesis / regulation of dendrite morphogenesis / tau-protein kinase activity / establishment of cell polarity / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / NF-kappaB binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / canonical Wnt signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / presynaptic modulation of chemical synaptic transmission / positive regulation of GTPase activity / positive regulation of protein export from nucleus / excitatory postsynaptic potential / negative regulation of cell migration / positive regulation of protein ubiquitination / hippocampus development / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / peptidyl-threonine phosphorylation / positive regulation of cell differentiation / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / positive regulation of protein-containing complex assembly / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / regulation of circadian rhythm / 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 / 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 / p53 binding / positive regulation of protein binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / insulin receptor signaling pathway / kinase activity
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 ...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-6QH / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsKurumbail, R.G. / Chang, J.S.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2016
Title: Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.
Authors: Liang, S.H. / Chen, J.M. / Normandin, M.D. / Chang, J.S. / Chang, G.C. / Taylor, C.K. / Trapa, P. / Plummer, M.S. / Para, K.S. / Conn, E.L. / Lopresti-Morrow, L. / Lanyon, L.F. / Cook, J.M. ...Authors: Liang, S.H. / Chen, J.M. / Normandin, M.D. / Chang, J.S. / Chang, G.C. / Taylor, C.K. / Trapa, P. / Plummer, M.S. / Para, K.S. / Conn, E.L. / Lopresti-Morrow, L. / Lanyon, L.F. / Cook, J.M. / Richter, K.E. / Nolan, C.E. / Schachter, J.B. / Janat, F. / Che, Y. / Shanmugasundaram, V. / Lefker, B.A. / Enerson, B.E. / Livni, E. / Wang, L. / Guehl, N.J. / Patnaik, D. / Wagner, F.F. / Perlis, R. / Holson, E.B. / Haggarty, S.J. / El Fakhri, G. / Kurumbail, R.G. / Vasdev, N.
History
DepositionMay 23, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2016Provider: repository / Type: Initial release

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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)85,1706
Polymers84,2542
Non-polymers9164
Water2,684149
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5853
Polymers42,1271
Non-polymers4582
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)42,5853
Polymers42,1271
Non-polymers4582
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.293, 99.907, 66.910
Angle α, β, γ (deg.)90.00, 102.90, 90.00
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: 42127.176 Da / Num. of mol.: 2 / Fragment: residues 28-382 / Mutation: V28G
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-6QH / 5-(3-chloranyl-4-methoxy-phenyl)-~{N}-[3-(1,2,4-triazol-1-yl)propyl]-1,3-oxazole-4-carboxamide


Mass: 361.783 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16ClN5O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 149 / 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: 2.68 Å3/Da / Density % sol: 54.07 % / Description: Chunky rectangular prism
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Protein storage conditions: 20 mM Tris pH 7.8, 5% (v/v) glycerol, 200 mM NaCl, 1 mM TCEP, 0.5 mM EDTA, 0.5% DMSO, and 0.2 mM PF-4802367, Well solution: 18-23% (w/v) PEG MME 5000, 100-150 mM ...Details: Protein storage conditions: 20 mM Tris pH 7.8, 5% (v/v) glycerol, 200 mM NaCl, 1 mM TCEP, 0.5 mM EDTA, 0.5% DMSO, and 0.2 mM PF-4802367, Well solution: 18-23% (w/v) PEG MME 5000, 100-150 mM ammonium sulfate, and 100 mM MES pH 6.5, Crystallization set-up: 0.5 + 0.5 uL drops over a well-solution of 200 uL

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 20, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 44180 / % possible obs: 95 % / Redundancy: 3.9 % / Biso Wilson estimate: 51.32 Å2 / Net I/σ(I): 11
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.15-2.212.50.466160.6
2.21-2.282.80.449184.2
2.28-2.373.40.429196.7
2.37-2.463.90.348199.8
2.46-2.574.20.2641100
2.57-2.714.20.1921100
2.71-2.884.20.1361100
2.88-3.14.30.0921100
3.1-3.414.30.0661100
3.41-3.914.30.051100
3.91-4.924.20.0431100
4.92-504.10.04198

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.2data extraction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→27.03 Å / Cor.coef. Fo:Fc: 0.9482 / Cor.coef. Fo:Fc free: 0.9353 / SU R Cruickshank DPI: 0.234 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.225 / SU Rfree Blow DPI: 0.177 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.2287 2121 5.03 %RANDOM
Rwork0.2038 ---
obs0.2051 42197 97.75 %-
Displacement parametersBiso mean: 58 Å2
Baniso -1Baniso -2Baniso -3
1--0.3464 Å20 Å21.0771 Å2
2---0.3281 Å20 Å2
3---0.6745 Å2
Refine analyzeLuzzati coordinate error obs: 0.302 Å
Refinement stepCycle: LAST / Resolution: 2.2→27.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5243 0 60 149 5452
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0095463HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.997447HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1821SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes115HARMONIC2
X-RAY DIFFRACTIONt_gen_planes823HARMONIC5
X-RAY DIFFRACTIONt_it5463HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.7
X-RAY DIFFRACTIONt_other_torsion17.44
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion715SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6189SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2287 132 5.2 %
Rwork0.223 2406 -
all0.2233 2538 -
obs--79.65 %
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)
12.6496-0.32931.44761.7129-0.53572.84870.19130.0056-0.3029-0.1631-0.00960.05880.3670.1228-0.1817-0.13910.0604-0.0132-0.1986-0.0508-0.231410.86981.10828.2357
21.0617-0.32730.44452.56790.36522.1771-0.16440.03340.18080.2905-0.08580.3403-0.0764-0.25090.2502-0.17440.00430.0115-0.1699-0.0644-0.11513.124728.58017.3219
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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