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- PDB-4afj: 5-aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK-3 inh... -

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Basic information

Entry
Database: PDB / ID: 4afj
Title5-aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK-3 inhibitors
Components
  • GLYCOGEN SYNTHASE KINASE-3 BETA
  • PROTO-ONCOGENE FRAT1
KeywordsTRANSFERASE/PEPTIDE / TRANSFERASE-PEPTIDE COMPLEX / KINASE
Function / homology
Function and homology information


negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 ...negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 / regulation of microtubule-based process / CRMPs in Sema3A signaling / regulation of protein export from nucleus / heart valve development / 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 / regulation of axon extension / Wnt signalosome / regulation of long-term synaptic potentiation / negative regulation of protein localization to nucleus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / positive regulation of cell-matrix adhesion / negative regulation of calcineurin-NFAT signaling cascade / dopamine receptor signaling pathway / regulation of dendrite morphogenesis / negative regulation of phosphoprotein phosphatase activity / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / glycogen metabolic process / molecular function inhibitor activity / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / protein kinase A catalytic subunit binding / NF-kappaB binding / canonical Wnt signaling pathway / Regulation of HSF1-mediated heat shock response / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / regulation of cellular response to heat / cellular response to retinoic acid / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / excitatory postsynaptic potential / presynaptic modulation of chemical synaptic transmission / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / hippocampus development / positive regulation of protein-containing complex assembly / 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 / 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 / regulation of circadian rhythm / beta-catenin binding / positive regulation of GTPase activity / circadian rhythm / positive regulation of canonical Wnt signaling pathway / neuron projection development / cellular response to amyloid-beta / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / insulin receptor signaling pathway / positive regulation of protein binding / kinase activity / postsynapse
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
Chem-SJJ / Glycogen synthase kinase-3 beta / Proto-oncogene FRAT1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.98 Å
AuthorsGentile, G. / Merlo, G. / Pozzan, A. / Bernasconi, G. / Bax, B. / Bamborough, P. / Bridges, A. / Carter, P. / Neu, M. / Yao, G. ...Gentile, G. / Merlo, G. / Pozzan, A. / Bernasconi, G. / Bax, B. / Bamborough, P. / Bridges, A. / Carter, P. / Neu, M. / Yao, G. / Brough, C. / Cutler, G. / Coffin, A. / Belyanskaya, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: 5-Aryl-4-Carboxamide-1,3-Oxazoles: Potent and Selective Gsk-3 Inhibitors.
Authors: Gentile, G. / Merlo, G. / Pozzan, A. / Bernasconi, G. / Bax, B. / Bamborough, P. / Bridges, A. / Carter, P. / Neu, M. / Yao, G. / Brough, C. / Cutler, G. / Coffin, A. / Belyanskaya, S.
History
DepositionJan 19, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 29, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2012Group: Other
Revision 1.2May 8, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3May 29, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / struct_biol / Item: _exptl_crystal_grow.method
Revision 1.4Dec 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_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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)92,20719
Polymers90,3684
Non-polymers1,84015
Water6,233346
1
A: GLYCOGEN SYNTHASE KINASE-3 BETA
X: PROTO-ONCOGENE FRAT1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0589
Polymers45,1842
Non-polymers8747
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2810 Å2
ΔGint-53.7 kcal/mol
Surface area17410 Å2
MethodPISA
2
B: GLYCOGEN SYNTHASE KINASE-3 BETA
Y: PROTO-ONCOGENE FRAT1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,15010
Polymers45,1842
Non-polymers9668
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2840 Å2
ΔGint-42.1 kcal/mol
Surface area17580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)152.317, 152.317, 199.054
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

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

#1: Protein GLYCOGEN SYNTHASE KINASE-3 BETA / / GSK3-BETA / SERINE/THREONINE-PROTEIN KINASE GSK3B


Mass: 41613.629 Da / Num. of mol.: 2 / Fragment: RESIDUES 27-393
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Protein/peptide PROTO-ONCOGENE FRAT1 / FREQUENTLY REARRANGED IN ADVANCED T-CELL LYMPHOMAS 1 / FRAT-1


Mass: 3570.161 Da / Num. of mol.: 2 / Fragment: RESIDUES 197-226
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q92837

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Non-polymers , 4 types, 361 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.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-SJJ / 5-(4-METHOXYPHENYL)-N-(PYRIDIN-4-YLMETHYL)-1,3-OXAZOLE-4-CARBOXAMIDE


Mass: 309.319 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15N3O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 346 / 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: 2.43 Å3/Da / Density % sol: 49.09 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20 DEGREES CELSIUS USING THE SITTING DRO METHOD 80 UL OF WELL SOLUTION AND 120 OR 100 NL OF PROTEIN AND 60 O 100 NL OF WELL SOLUTION (2 + 1 AND 1 + 1 PROTEIN:WELL RATIO) 30% PEG 3350, 10% ...Details: 20 DEGREES CELSIUS USING THE SITTING DRO METHOD 80 UL OF WELL SOLUTION AND 120 OR 100 NL OF PROTEIN AND 60 O 100 NL OF WELL SOLUTION (2 + 1 AND 1 + 1 PROTEIN:WELL RATIO) 30% PEG 3350, 10% GLYCEROL, 0.1 M BISTRIS PH6.5 AND 0.2 M AMMONIUM SULPHATE, CONTAINING 0.1 M COMPOUND (AND 1% DMSO).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 1.9→40 Å / Num. obs: 60045 / % possible obs: 97.3 % / Observed criterion σ(I): 0 / Redundancy: 6.3 % / Biso Wilson estimate: 29.99 Å2 / Rmerge(I) obs: 0.073 / Net I/σ(I): 20.7
Reflection shellResolution: 1.98→2.01 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 2.7 / % possible all: 99

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1GNG

1gng


Resolution: 1.98→36.65 Å / Cor.coef. Fo:Fc: 0.9555 / Cor.coef. Fo:Fc free: 0.9363 / SU R Cruickshank DPI: 0.155 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.156 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.142
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY.
RfactorNum. reflection% reflectionSelection details
Rfree0.2161 2429 4.05 %RANDOM
Rwork0.1778 ---
obs0.1793 60019 97.25 %-
Displacement parametersBiso mean: 37.35 Å2
Baniso -1Baniso -2Baniso -3
1-0.8696 Å20 Å20 Å2
2--0.8696 Å20 Å2
3----1.7391 Å2
Refine analyzeLuzzati coordinate error obs: 0.238 Å
Refinement stepCycle: LAST / Resolution: 1.98→36.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5855 0 118 346 6319
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016322HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.018612HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2161SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes130HARMONIC2
X-RAY DIFFRACTIONt_gen_planes937HARMONIC5
X-RAY DIFFRACTIONt_it6322HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion17.3
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion803SEMIHARMONIC5
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_contact7571SEMIHARMONIC4
LS refinement shellResolution: 1.98→2.03 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.253 171 3.83 %
Rwork0.2021 4291 -
all0.2041 4462 -
obs--97.25 %
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)
13.46841.72051.3032.76310.82523.849-0.24890.5621-0.0758-0.33480.1732-0.0776-0.0740.21910.07570.2293-0.1218-0.04710.31540.00110.166194.362521.2946-15.4879
21.48050.03150.45541.43830.03691.0067-0.1022-0.04140.1271-0.09620.0367-0.0550.0045-0.03170.06550.1422-0.0305-0.02210.10670.0010.1176107.851828.73917.9341
31.384-1.2536-0.8732.73350.92294.0291-0.0087-0.22130.07940.2950.0128-0.02460.00170.1048-0.00410.2360.06220.0420.1932-0.00820.211697.696965.250.1062
41.09450.1077-0.08862.13640.01111.157-0.04120.0742-0.04390.09230.077-0.1699-0.1349-0.0431-0.03580.12710.0311-0.01710.07540.00160.1235109.281355.983325.7752
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(CHAIN A AND (RESSEQ 36:134 OR RESSEQ 1391))
2X-RAY DIFFRACTION2(CHAIN A AND (RESSEQ 135:384 OR RESSEQ 1385)) OR (CHAIN X AND RESSEQ 200:222)
3X-RAY DIFFRACTION3(CHAIN B AND (RESSEQ 35:134 OR RESSEQ 1392))
4X-RAY DIFFRACTION4(CHAIN B AND (RESSEQ 135:383 OR RESSEQ 1385)) OR (CHAIN Y AND RESSEQ 200:222)

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