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- PDB-4acg: GSK3b in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4acg
TitleGSK3b in complex with inhibitor
ComponentsGLYCOGEN SYNTHASE KINASE-3 BETA
KeywordsTRANSFERASE
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 / 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 / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / ER overload response / glycogen metabolic process / establishment of cell polarity / regulation of neuron projection development / protein kinase A catalytic subunit binding / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / Regulation of HSF1-mediated heat shock response / canonical Wnt signaling pathway / NF-kappaB binding / positive regulation of protein binding / 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 / positive regulation of protein ubiquitination / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of autophagy / presynaptic modulation of chemical synaptic transmission / Transcriptional and post-translational regulation of MITF-M expression and activity / Ubiquitin-dependent degradation of Cyclin D / regulation of microtubule cytoskeleton organization / response to endoplasmic reticulum stress / negative regulation of cell migration / positive regulation of protein export from nucleus / excitatory postsynaptic potential / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / mitochondrion organization / positive regulation of cell differentiation / hippocampus development / Degradation of beta-catenin by the destruction complex / positive regulation of protein-containing complex assembly / negative regulation of canonical Wnt signaling pathway / regulation of circadian rhythm / circadian rhythm / beta-catenin binding / peptidyl-serine phosphorylation / B-WICH complex positively regulates rRNA expression / tau protein binding / Regulation of RUNX2 expression and activity / Wnt signaling pathway / cellular response to amyloid-beta / neuron projection development / positive regulation of protein catabolic process / p53 binding / kinase activity / insulin receptor signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of neuron apoptotic process
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-6LQ / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsXue, Y. / Ormo, M.
CitationJournal: J. Med. Chem. / Year: 2012
Title: Discovery of novel potent and highly selective glycogen synthase kinase-3 beta (GSK3 beta ) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.
Authors: Berg, S. / Bergh, M. / Hellberg, S. / Hogdin, K. / Lo-Alfredsson, Y. / Soderman, P. / von Berg, S. / Weigelt, T. / Ormo, M. / Xue, Y. / Tucker, J. / Neelissen, J. / Jerning, E. / Nilsson, Y. / Bhat, R.
History
DepositionDec 15, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2012Group: Database references
Revision 1.2Feb 14, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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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)105,2214
Polymers104,1502
Non-polymers1,0712
Water8,737485
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2560 Å2
ΔGint-12.1 kcal/mol
Surface area31770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.976, 83.881, 177.461
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: 52074.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: TRICHOPLUSIA NI (cabbage looper)
References: UniProt: P49841, non-specific serine/threonine protein kinase, tau-protein kinase
#2: Chemical ChemComp-6LQ / 2-AMINO-5-{4-[(4-METHYLPIPERAZIN-1-YL)SULFONYL]PHENYL}-N-[4-(PYRROLIDIN-1-YLMETHYL)PYRIDIN-3-YL]PYRIDINE-3-CARBOXAMIDE


Mass: 535.661 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 485 / 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: 2.99 Å3/Da / Density % sol: 57.99 % / Description: NONE

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Data collection

DiffractionMean temperature: 173 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. obs: 38081 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 6.2 % / Biso Wilson estimate: 54.63 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 14.3
Reflection shellResolution: 2.6→2.75 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 2.3 / % possible all: 94.2

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→19.97 Å / Cor.coef. Fo:Fc: 0.9274 / Cor.coef. Fo:Fc free: 0.8984 / SU R Cruickshank DPI: 0.31 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.34 / SU Rfree Blow DPI: 0.24 / SU Rfree Cruickshank DPI: 0.236
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2249 1520 4.01 %RANDOM
Rwork0.1747 ---
obs0.1767 37947 99.06 %-
Displacement parametersBiso mean: 52.24 Å2
Baniso -1Baniso -2Baniso -3
1--13.9651 Å20 Å20 Å2
2---1.1527 Å20 Å2
3---15.1178 Å2
Refine analyzeLuzzati coordinate error obs: 0.291 Å
Refinement stepCycle: LAST / Resolution: 2.6→19.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5610 0 76 485 6171
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015836HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.147946HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1986SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes126HARMONIC2
X-RAY DIFFRACTIONt_gen_planes840HARMONIC5
X-RAY DIFFRACTIONt_it5836HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.94
X-RAY DIFFRACTIONt_other_torsion19.49
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion750SEMIHARMONIC5
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_contact6798SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.67 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.322 111 4.03 %
Rwork0.2261 2641 -
all0.2302 2752 -
obs--99.06 %

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