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- PDB-3i4b: Crystal structure of GSK3b in complex with a pyrimidylpyrrole inh... -

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Basic information

Entry
Database: PDB / ID: 3i4b
TitleCrystal structure of GSK3b in complex with a pyrimidylpyrrole inhibitor
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase / gsk3b / ERK / Pyrimidyl pyrrole / Alternative splicing / ATP-binding / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Wnt signaling pathway
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 / 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 ...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-Z48 / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsTer Haar, E.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control.
Authors: Aronov, A.M. / Tang, Q. / Martinez-Botella, G. / Bemis, G.W. / Cao, J. / Chen, G. / Ewing, N.P. / Ford, P.J. / Germann, U.A. / Green, J. / Hale, M.R. / Jacobs, M. / Janetka, J.W. / Maltais, ...Authors: Aronov, A.M. / Tang, Q. / Martinez-Botella, G. / Bemis, G.W. / Cao, J. / Chen, G. / Ewing, N.P. / Ford, P.J. / Germann, U.A. / Green, J. / Hale, M.R. / Jacobs, M. / Janetka, J.W. / Maltais, F. / Markland, W. / Namchuk, M.N. / Nanthakumar, S. / Poondru, S. / Straub, J. / ter Haar, E. / Xie, X.
History
DepositionJul 1, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Apr 3, 2024Group: Refinement description / Category: 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)93,0564
Polymers92,2292
Non-polymers8272
Water13,241735
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3320 Å2
ΔGint-13.8 kcal/mol
Surface area30110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.750, 86.100, 178.290
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glycogen synthase kinase-3 beta / GSK-3 beta


Mass: 46114.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Cell line (production host): high-5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49841, tau-protein kinase
#2: Chemical ChemComp-Z48 / N-[(1S)-2-hydroxy-1-phenylethyl]-4-[5-methyl-2-(phenylamino)pyrimidin-4-yl]-1H-pyrrole-2-carboxamide


Mass: 413.472 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 735 / 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: 3.44 Å3/Da / Density % sol: 64.28 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 20% PEG 3350, 0.2M Potassium fluoride, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 123 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jul 10, 2001 / Details: mirrors
RadiationMonochromator: osmic mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 55110 / % possible obs: 95.8 % / Observed criterion σ(I): 2 / Redundancy: 6.3 % / Biso Wilson estimate: 37.8 Å2 / Rmerge(I) obs: 0.057 / Χ2: 1.291 / Net I/σ(I): 18.3
Reflection shellResolution: 2.3→2.38 Å / Rmerge(I) obs: 0.262 / Mean I/σ(I) obs: 3.8 / Num. unique all: 4467 / Χ2: 1.265 / % possible all: 78.9

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
BUSTER-TNTv. 1.3.1refinement
PDB_EXTRACT3.005data extraction
CrystalCleardata collection
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In house GSK3b structure

Resolution: 2.3→37.35 Å / Occupancy max: 1 / Occupancy min: 1 / Isotropic thermal model: anisotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: RESTRAINT 1: csdx_protgeo.dat (V1.40) 20080428. RESTRAINT 2: nuclgeo.dat (V1.10) 20070206. RESTRAINT 3: bcorrel.dat (V1.15) 20080423. RESTRAINT 4: contact.dat (V1.15) 20070207. RESTRAINT 5: ...Details: RESTRAINT 1: csdx_protgeo.dat (V1.40) 20080428. RESTRAINT 2: nuclgeo.dat (V1.10) 20070206. RESTRAINT 3: bcorrel.dat (V1.15) 20080423. RESTRAINT 4: contact.dat (V1.15) 20070207. RESTRAINT 5: assume.dat (V1.8) 20070124. NCS MODEL: RESTRAINT LSSR. TARGET RESTRAINT: NONE.
RfactorNum. reflection% reflectionSelection details
Rfree0.222 2635 5.1 %RANDOM
Rwork0.179 ---
all0.181 54328 --
obs0.181 54328 90.68 %-
Displacement parametersBiso max: 122.75 Å2 / Biso mean: 36.938 Å2 / Biso min: 9.86 Å2
Baniso -1Baniso -2Baniso -3
1--3.34 Å20 Å20 Å2
2---6.291 Å20 Å2
3---9.631 Å2
Refinement stepCycle: LAST / Resolution: 2.3→37.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5545 0 62 735 6342
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.01257572
X-RAY DIFFRACTIONt_angle_deg1.22377952
X-RAY DIFFRACTIONt_dihedral_angle_d17.62110880
X-RAY DIFFRACTIONt_trig_c_planes0.0091202
X-RAY DIFFRACTIONt_gen_planes0.0198475
X-RAY DIFFRACTIONt_it1.225575720
X-RAY DIFFRACTIONt_nbd0.11665
LS refinement shellResolution: 2.3→2.44 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.269 332 5.07 %
Rwork0.232 6216 -
all0.234 6548 -
obs--90.68 %

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