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- PDB-3zrk: Identification of 2-(4-pyridyl)thienopyridinones as GSK-3beta inh... -

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Basic information

Entry
Database: PDB / ID: 3zrk
TitleIdentification of 2-(4-pyridyl)thienopyridinones as GSK-3beta inhibitors
Components
  • GLYCOGEN SYNTHASE KINASE-3 BETA
  • PROTO-ONCOGENE FRAT1
KeywordsTRANSFERASE/PEPTIDE / TRANSFERASE-PEPTIDE COMPLEX / KINASE
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 / dopamine receptor signaling pathway / negative regulation of phosphoprotein phosphatase activity / regulation of dendrite morphogenesis / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / glycogen metabolic process / molecular function inhibitor activity / 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 / canonical Wnt signaling pathway / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / 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 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 / tau protein binding / negative regulation of canonical Wnt signaling pathway / B-WICH complex positively regulates rRNA expression / regulation of circadian rhythm / beta-catenin binding / positive regulation of GTPase activity / 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 / positive regulation of canonical Wnt signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / positive regulation of protein binding / insulin receptor signaling pathway
Similarity search - Function
Glycogen synthase kinase-3 binding protein / Glycogen synthase kinase-3 binding / 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 ...Glycogen synthase kinase-3 binding protein / Glycogen synthase kinase-3 binding / 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
2-(4-PYRIDINYL)FURO[3,2-C]PYRIDIN-4(5H)-ONE / Glycogen synthase kinase-3 beta / Proto-oncogene FRAT1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.37 Å
AuthorsGentile, G. / Bernasconi, G. / Pozzan, A. / Merlo, G. / Marzorati, P. / Bamborough, P. / Bax, B. / Bridges, A. / Brough, C. / Carter, P. ...Gentile, G. / Bernasconi, G. / Pozzan, A. / Merlo, G. / Marzorati, P. / Bamborough, P. / Bax, B. / Bridges, A. / Brough, C. / Carter, P. / Cutler, G. / Neu, M. / Takada, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Identification of 2-(4-Pyridyl)Thienopyridinones as Gsk-3Beta Inhibitors.
Authors: Gentile, G. / Bernasconi, G. / Pozzan, A. / Merlo, G. / Marzorati, P. / Bamborough, P. / Bax, B. / Bridges, A. / Brough, C. / Carter, P. / Cutler, G. / Neu, M. / Takada, M.
History
DepositionJun 16, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 29, 2011Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2012Group: Database references / Version format compliance
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / 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_conn.pdbx_leaving_atom_flag / _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

Downloads & links

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Assembly

Deposited unit
A: GLYCOGEN SYNTHASE KINASE-3 BETA
B: GLYCOGEN SYNTHASE KINASE-3 BETA
X: PROTO-ONCOGENE FRAT1
Y: PROTO-ONCOGENE FRAT1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,89415
Polymers91,6174
Non-polymers1,27711
Water3,765209
1
A: GLYCOGEN SYNTHASE KINASE-3 BETA
X: PROTO-ONCOGENE FRAT1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3977
Polymers45,8092
Non-polymers5895
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint-53.5 kcal/mol
Surface area17870 Å2
MethodPISA
2
B: GLYCOGEN SYNTHASE KINASE-3 BETA
Y: PROTO-ONCOGENE FRAT1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4978
Polymers45,8092
Non-polymers6896
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1970 Å2
ΔGint-42.6 kcal/mol
Surface area17900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)151.896, 151.896, 201.119
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11B-1392-

SO4

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABXY

#1: Protein GLYCOGEN SYNTHASE KINASE-3 BETA / / GSK-3 BETA


Mass: 42036.117 Da / Num. of mol.: 2 / Fragment: RESIDUES 23-393
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P49841, tau-protein kinase
#2: Protein/peptide PROTO-ONCOGENE FRAT1 / FRAT / FREQUENTLY REARRANGED IN ADVANCED T-CELL LYMPHOMAS 1 / FRAT-1


Mass: 3772.434 Da / Num. of mol.: 2 / Fragment: RESIDUES 197-226
Source method: isolated from a genetically manipulated source
Details: FRATTIDE SEQUENCE CO-EXPRESSED IN BACULOVIRUS (DUAL EXPRESSION).
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q92837

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Non-polymers , 4 types, 220 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-ZRK / 2-(4-PYRIDINYL)FURO[3,2-C]PYRIDIN-4(5H)-ONE


Mass: 212.204 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H8N2O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.21 Å3/Da / Density % sol: 44.27 % / Description: NONE
Crystal growDetails: 0.2M AMMONIUM SULFATE, 0.1M BISTRIS PH6.5, 30% PEG 3350, 10% GLYCEROL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.07225
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07225 Å / Relative weight: 1
ReflectionResolution: 2.37→40 Å / Num. obs: 36362 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 7 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 28.2
Reflection shellResolution: 2.37→2.41 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 4.3 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.3.0006refinement
HKLdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1GNG

1gng


Resolution: 2.37→20 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.927 / SU B: 7.152 / SU ML: 0.173 / Cross valid method: THROUGHOUT / ESU R: 0.401 / ESU R Free: 0.251 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24274 1830 5 %RANDOM
Rwork0.19834 ---
obs0.20062 34453 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 45.527 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å2-0.16 Å20 Å2
2---0.31 Å20 Å2
3---0.47 Å2
Refinement stepCycle: LAST / Resolution: 2.37→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5905 0 80 209 6194
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0226298
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1291.998594
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7745770
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.60522.975279
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.244151037
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0021552
X-RAY DIFFRACTIONr_chiral_restr0.0830.2954
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024870
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1980.22881
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3020.24311
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.130.2317
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1960.257
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1670.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.88323940
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.75756251
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.31362656
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.41582343
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.37→2.431 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 133 -
Rwork0.242 2488 -
obs--99.62 %

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