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- PDB-6v6l: Co-structure of human glycogen synthase kinase beta with 1-(6-((2... -

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Basic information

Entry
Database: PDB / ID: 6v6l
TitleCo-structure of human glycogen synthase kinase beta with 1-(6-((2-((6-amino-5-nitropyridin-2-yl)amino)ethyl)amino)-2-(2,4-dichlorophenyl)pyridin-3-yl)-4-methylpiperazin-2-one
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase
Function / homology
Function and homology information


negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 ...negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 / regulation of microtubule-based process / heart valve development / 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 / 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 / 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 / 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 / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / 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 cell differentiation / positive regulation of protein-containing complex assembly / 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 / Degradation of beta-catenin by the destruction complex / tau protein binding / negative regulation of canonical Wnt signaling pathway / regulation of circadian rhythm / B-WICH complex positively regulates rRNA expression / beta-catenin binding / positive regulation of GTPase activity / circadian rhythm / cellular response to amyloid-beta / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / neuron projection development / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / positive regulation of protein binding / insulin receptor signaling pathway / kinase activity / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / peptidyl-serine phosphorylation
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / 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
Similarity search - Domain/homology
PHOSPHATE ION / Chem-QQA / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsBussiere, D.E. / Fang, E. / Shu, W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors.
Authors: Ramurthy, S. / Pfister, K.B. / Boyce, R.S. / Brown, S.P. / Costales, A.Q. / Desai, M.C. / Fang, E. / Levine, B.H. / Ng, S.C. / Nuss, J.M. / Ring, D.B. / Shafer, C.M. / Shu, W. / Subramanian, ...Authors: Ramurthy, S. / Pfister, K.B. / Boyce, R.S. / Brown, S.P. / Costales, A.Q. / Desai, M.C. / Fang, E. / Levine, B.H. / Ng, S.C. / Nuss, J.M. / Ring, D.B. / Shafer, C.M. / Shu, W. / Subramanian, S. / Wagman, A.S. / Wang, H. / Bussiere, D.E.
History
DepositionDec 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Feb 5, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 2.0Jun 29, 2022Group: Database references / Non-polymer description / Structure summary
Category: chem_comp / database_2 / entity
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight
Revision 2.1Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5083
Polymers46,8811
Non-polymers6262
Water7,620423
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.080, 64.760, 58.250
Angle α, β, γ (deg.)90.000, 100.130, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 46881.195 Da / Num. of mol.: 1
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-QQA / 1-(6-((2-((6-amino-5-nitropyridin-2-yl)amino)ethyl)amino)-2-(2,4-dichlorophenyl)pyridin-3-yl)-4-methylpiperazin-2-one


Mass: 531.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24Cl2N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


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


Mass: 18.015 Da / Num. of mol.: 423 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.12 Å3/Da / Density % sol: 42.06 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / Details: 7-12% (w:v) PEG 6000 and 5-8% MPD (v:v)

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Data collection

DiffractionMean temperature: 290 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Nov 1, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.19→25.01 Å / Num. obs: 20146 / % possible obs: 96.9 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.109 / Net I/σ(I): 7.3
Reflection shellResolution: 2.19→2.25 Å / Rmerge(I) obs: 0.614 / Num. unique obs: 1514

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
xia2data scaling
CrystalCleardata collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6B8J

6b8j


Resolution: 2.19→24.17 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.914 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.351 / SU Rfree Blow DPI: 0.215
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1015 5.04 %RANDOM
Rwork0.203 ---
obs0.204 20146 96.4 %-
Displacement parametersBiso max: 92.32 Å2 / Biso mean: 29.4 Å2 / Biso min: 12.51 Å2
Baniso -1Baniso -2Baniso -3
1--0.0352 Å20 Å2-4.6723 Å2
2---3.3506 Å20 Å2
3---3.3858 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.19→24.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2683 0 41 423 3147
Biso mean--28.32 45.61 -
Num. residues----344
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1149SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes837HARMONIC5
X-RAY DIFFRACTIONt_it5394HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion368SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6157SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5394HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg9726HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion2.58
X-RAY DIFFRACTIONt_other_torsion15.03
LS refinement shellResolution: 2.19→2.2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2187 24 5.96 %
Rwork0.232 379 -
all0.2313 403 -
obs--98.2 %
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)
10.3263-0.26320.12640.1616-0.00370.341-00.0028-0.0035-0.002-0.0006-0.0030.00670.00330.00070.00910.00840.00730.01940.00360.01512.2541-1.9476-21.033
20.5242-0.4323-0.15820.2553-0.2243-0.07330.00190.0005-0.0025-0.0026-0.0037-0.0013-0.00230.00380.0018-0.00840.02090.010.00860.00440.00667.91570.9062-16.5484
30.8969-0.1119-0.42560.0097-0.5373-0.06150.00310.0062-0.00370.00160.0001-0.0008-0.00180.0074-0.0032-0.00420.022500.00240.0230.01151.35235.2384-17.9573
40.8617-0.5103-0.22520.20360.34780.5561-0.0007-0.00970.00690.0151-0.0052-0.00880.00680.01060.006-0.00010.0014-0.01280.00010.0072-0.0058-11.2479.5168-8.2644
50.11830.0379-0.11350.38410.29680.1167-0.0017-0.00890.0020.00640.0005-0.00120.00080.00180.00110.0133-0.00490.00060.0043-0.0047-0.0043-22.280417.87255.2556
60.23440.02710.04070.0710.2590.42360.00190.01090.0037-0.0039-0.00370.0032-0.0068-0.00660.00180.01520.0069-0.0033-0.00050.00650.0038-23.853811.274-13.19
70.20870.03330.11220.26240.17920.3763-0.00090.0144-0.0016-0.0066-0.00380.00240.00250.00110.00480.0167-0.0077-0.0030.00170.00030.0023-21.5953-0.901-25.475
80.0023-0.0078-0.003500.0016-0.00130.000100.00030.0005-0.0002-0.0002-0.0004-0.00020-0.00370.00410.0041-0.0029-0.0014-0.00042.497410.1677-17.4046
90.0002-0.0002-0.00020-0.0003-0.00010-0-000-0.000100.0001-00.0006-0-0.0008-0.00030.0011-0.0008-2.81380.30423.3028
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|37 - A|67 }A37 - 67
2X-RAY DIFFRACTION2{ A|68 - A|100 }A68 - 100
3X-RAY DIFFRACTION3{ A|101 - A|154 }A101 - 154
4X-RAY DIFFRACTION4{ A|155 - A|273 }A155 - 273
5X-RAY DIFFRACTION5{ A|274 - A|304 }A274 - 304
6X-RAY DIFFRACTION6{ A|305 - A|344 }A305 - 344
7X-RAY DIFFRACTION7{ A|345 - A|384 }A345 - 384
8X-RAY DIFFRACTION8{ A|501 - A|501 }B1
9X-RAY DIFFRACTION9{ A|502 - A|502 }E1

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