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- PDB-5t31: Exploiting an Asp-Glu switch in Glycogen Synthase Kinase 3 to des... -

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Basic information

Entry
Database: PDB / ID: 5t31
TitleExploiting an Asp-Glu switch in Glycogen Synthase Kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE/TRANSFERASE inhibitor / glycogen synthase 3 alpha beta mutant / 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 / tau-protein kinase / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / 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 / cellular response to interleukin-3 / Maturation of nucleoprotein / 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 / Regulation of HSF1-mediated heat shock response / NF-kappaB binding / canonical Wnt signaling pathway / negative regulation of osteoblast differentiation / 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 / 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 / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / excitatory postsynaptic potential / hippocampus development / mitochondrion organization / positive regulation of cell differentiation / positive regulation of protein-containing complex assembly / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / negative regulation of canonical Wnt signaling pathway / circadian rhythm / regulation of circadian rhythm / Degradation of beta-catenin by the destruction complex / beta-catenin binding / peptidyl-serine phosphorylation / B-WICH complex positively regulates rRNA expression / tau protein binding / Wnt signaling pathway / cellular response to amyloid-beta / neuron projection development / Regulation of RUNX2 expression and activity / 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-6VL / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsStein, A.J. / Holson, E.B. / Wagner, F.F. / Cambell, A.J.
CitationJournal: Sci Transl Med / Year: 2018
Title: Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.
Authors: Wagner, F.F. / Benajiba, L. / Campbell, A.J. / Weiwer, M. / Sacher, J.R. / Gale, J.P. / Ross, L. / Puissant, A. / Alexe, G. / Conway, A. / Back, M. / Pikman, Y. / Galinsky, I. / DeAngelo, D. ...Authors: Wagner, F.F. / Benajiba, L. / Campbell, A.J. / Weiwer, M. / Sacher, J.R. / Gale, J.P. / Ross, L. / Puissant, A. / Alexe, G. / Conway, A. / Back, M. / Pikman, Y. / Galinsky, I. / DeAngelo, D.J. / Stone, R.M. / Kaya, T. / Shi, X. / Robers, M.B. / Machleidt, T. / Wilkinson, J. / Hermine, O. / Kung, A. / Stein, A.J. / Lakshminarasimhan, D. / Hemann, M.T. / Scolnick, E. / Zhang, Y.L. / Pan, J.Q. / Stegmaier, K. / Holson, E.B.
History
DepositionAug 24, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.0May 8, 2019Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / citation_author / entity / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / struct_site
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.type_symbol / _chem_comp.id / _chem_comp.name / _citation_author.identifier_ORCID / _entity.pdbx_description / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _struct_site.details / _struct_site.pdbx_auth_comp_id
Revision 2.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 2.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)94,4334
Polymers93,7902
Non-polymers6432
Water00
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2172
Polymers46,8951
Non-polymers3211
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2172
Polymers46,8951
Non-polymers3211
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)107.957, 84.223, 117.218
Angle α, β, γ (deg.)90.00, 94.69, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 46895.219 Da / Num. of mol.: 2 / Mutation: D133E
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-6VL / (4~{S})-4-ethyl-7,7-dimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one


Mass: 321.416 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23N3O
Has protein modificationY

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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: 2.76 Å3/Da / Density % sol: 55.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 20% PEG MME 5,000 and 0.1 M Bis-Tris pH 6.5

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97875 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97875 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 24568 / % possible obs: 99 % / Redundancy: 3.8 % / Net I/σ(I): 13.3
Reflection shellResolution: 2.85→2.95 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 1.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4PTE

4pte


Resolution: 2.85→47.41 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.906 / SU B: 18.442 / SU ML: 0.332 / Cross valid method: THROUGHOUT / ESU R: 0.964 / ESU R Free: 0.376 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26797 1206 5.1 %RANDOM
Rwork0.196 ---
obs0.19962 22658 97.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 79.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20.05 Å2
2---0.01 Å20 Å2
3----0.02 Å2
Refinement stepCycle: 1 / Resolution: 2.85→47.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5155 0 48 0 5203
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0195335
X-RAY DIFFRACTIONr_bond_other_d0.0030.025000
X-RAY DIFFRACTIONr_angle_refined_deg1.7091.9967312
X-RAY DIFFRACTIONr_angle_other_deg1.027311473
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.55663
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.67623.645214
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.21515798
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3211531
X-RAY DIFFRACTIONr_chiral_restr0.0890.2849
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0215988
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021181
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it5.718.1132672
X-RAY DIFFRACTIONr_mcbond_other5.6998.1152669
X-RAY DIFFRACTIONr_mcangle_it8.50712.1683327
X-RAY DIFFRACTIONr_mcangle_other8.50812.1693328
X-RAY DIFFRACTIONr_scbond_it5.3588.2712663
X-RAY DIFFRACTIONr_scbond_other5.3578.272664
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.99512.3093986
X-RAY DIFFRACTIONr_long_range_B_refined10.57464.1355797
X-RAY DIFFRACTIONr_long_range_B_other10.57364.1365798
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.851→2.925 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 67 -
Rwork0.288 1429 -
obs--83.9 %

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