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- PDB-3l1s: 3-Aryl-4-(arylhydrazono)-1H-pyrazol-5-ones: Highly ligand efficie... -

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Basic information

Entry
Database: PDB / ID: 3l1s
Title3-Aryl-4-(arylhydrazono)-1H-pyrazol-5-ones: Highly ligand efficient and potent inhibitors of GSK3
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase / pyrazole / GSK3 / ATP-binding / Nucleotide-binding / 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 / beta-catenin destruction complex disassembly / negative regulation of mesenchymal stem cell differentiation / 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 ...regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / beta-catenin destruction complex disassembly / negative regulation of mesenchymal stem cell differentiation / 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 TOR signaling / negative regulation of protein localization to nucleus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / regulation of long-term synaptic potentiation / 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 / establishment of cell polarity / tau-protein kinase activity / regulation of axonogenesis / regulation of dendrite morphogenesis / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / NF-kappaB binding / Transcriptional and post-translational regulation of MITF-M expression and activity / 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 / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / presynaptic modulation of chemical synaptic transmission / excitatory postsynaptic potential / positive regulation of protein export from nucleus / positive regulation of GTPase activity / negative regulation of cell migration / mitochondrion organization / 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 / negative regulation of canonical Wnt signaling pathway / Degradation of beta-catenin by the destruction complex / tau protein binding / regulation of circadian rhythm / B-WICH complex positively regulates rRNA expression / 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 / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of protein binding / insulin receptor signaling pathway / presynapse / 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 ...: / 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
PHOSPHATE ION / Chem-Z92 / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsHaar, T.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: 3-Aryl-4-(arylhydrazono)-1H-pyrazol-5-ones: Highly ligand efficient and potent inhibitors of GSK3beta.
Authors: Arnost, M. / Pierce, A. / Haar, E.T. / Lauffer, D. / Madden, J. / Tanner, K. / Green, J.
History
DepositionDec 14, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type / _software.version
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

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)93,0415
Polymers92,2292
Non-polymers8133
Water7,332407
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4732
Polymers46,1141
Non-polymers3591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5683
Polymers46,1141
Non-polymers4542
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.600, 84.800, 178.000
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


Mass: 46114.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Plasmid: pBEV / Cell line (production host): Insect cell / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): High-5 Cells / References: UniProt: P49841, tau-protein kinase
#2: Chemical ChemComp-Z92 / (4E)-4-[(4-chlorophenyl)hydrazono]-5-(3,4-dimethoxyphenyl)-2,4-dihydro-3H-pyrazol-3-one / (4Z)-4-[(4-chlorophenyl)hydrazono]-5-(3,4-dimethoxyphenyl)-2H-pyrazol-3-one


Mass: 358.779 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15ClN4O3
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 407 / 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: 3.33 Å3/Da / Density % sol: 63.06 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 20% PEG3350, 0.2M KF, 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 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 13, 2001
RadiationMonochromator: osmic mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 28035 / % possible obs: 97.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 3 / Rmerge(I) obs: 0.094 / Χ2: 1.086 / Net I/σ(I): 10.4
Reflection shellResolution: 2.9→3 Å / Rmerge(I) obs: 0.342 / Mean I/σ(I) obs: 3.2 / Num. unique all: 2760 / Χ2: 0.976 / % possible all: 98.2

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Processing

Software
NameVersionClassificationNB
BUSTER2.9.2refinement
SCALEPACKdata scaling
TNTrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data reduction
HKL-2000data scaling
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: previous gsk3b structure

Resolution: 2.9→39.18 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.878 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.232 1335 5.02 %RANDOM
Rwork0.184 ---
all0.186 27903 --
obs0.186 27903 --
Displacement parametersBiso max: 168.37 Å2 / Biso mean: 38.217 Å2 / Biso min: 7.57 Å2
Baniso -1Baniso -2Baniso -3
1--5.105 Å20 Å20 Å2
2---6.326 Å20 Å2
3---11.431 Å2
Refine analyzeLuzzati coordinate error obs: 0.342 Å
Refinement stepCycle: LAST / Resolution: 2.9→39.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5155 0 55 407 5617
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_bond_d0.01
X-RAY DIFFRACTIONo_angle_deg1.12
X-RAY DIFFRACTIONo_dihedral_angle_d2.98
X-RAY DIFFRACTIONo_dihedral_angle_o18.53
LS refinement shellResolution: 2.9→3.02 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.322 143 5.07 %
Rwork0.245 2676 -
all0.249 2819 -
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)
11.4358-0.11360.07441.3789-0.00962.0917-0.06690.09590.0485-0.08110.06-0.05370.2016-0.06780.007-0.0536-0.06920.014-0.0931-0.0338-0.138727.544236.984149.7079
21.4648-0.1207-0.20371.06520.49951.90630.0523-0.03410.06690.021-0.0325-0.05580.1973-0.059-0.0198-0.1618-0.03970.0233-0.0015-0.0172-0.115321.60349.3685.7822
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth seq-ID
1X-RAY DIFFRACTION1{ A|25 - A|31 A|35 - A|118 A|126 - A|285 A|299 - A|384 }25 - 31
2X-RAY DIFFRACTION1{ A|25 - A|31 A|35 - A|118 A|126 - A|285 A|299 - A|384 }35 - 118
3X-RAY DIFFRACTION1{ A|25 - A|31 A|35 - A|118 A|126 - A|285 A|299 - A|384 }126 - 285
4X-RAY DIFFRACTION1{ A|25 - A|31 A|35 - A|118 A|126 - A|285 A|299 - A|384 }299 - 384
5X-RAY DIFFRACTION2{ B|36 - B|119 B|122 - B|285 B|301 - B|382 }36 - 119
6X-RAY DIFFRACTION2{ B|36 - B|119 B|122 - B|285 B|301 - B|382 }122 - 285
7X-RAY DIFFRACTION2{ B|36 - B|119 B|122 - B|285 B|301 - B|382 }301 - 382

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