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- PDB-7sxg: BIO-8546 bound GSK3alpha-axin complex -

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Basic information

Entry
Database: PDB / ID: 7sxg
TitleBIO-8546 bound GSK3alpha-axin complex
Components
  • Axin peptide
  • Glycogen synthase kinase-3 alpha
KeywordsHYDROLASE / kinase
Function / homology
Function and homology information


negative regulation of UDP-glucose catabolic process / negative regulation of glycogen synthase activity, transferring glucose-1-phosphate / positive regulation of glycogen (starch) synthase activity / : / positive regulation of heart contraction / : / cardiac left ventricle morphogenesis / negative regulation of glycogen (starch) synthase activity / proximal dendrite / regulation of autophagy of mitochondrion ...negative regulation of UDP-glucose catabolic process / negative regulation of glycogen synthase activity, transferring glucose-1-phosphate / positive regulation of glycogen (starch) synthase activity / : / positive regulation of heart contraction / : / cardiac left ventricle morphogenesis / negative regulation of glycogen (starch) synthase activity / proximal dendrite / regulation of autophagy of mitochondrion / negative regulation of type B pancreatic cell development / negative regulation of cell growth involved in cardiac muscle cell development / negative regulation of dendrite development / negative regulation of glycogen biosynthetic process / regulation of systemic arterial blood pressure / XBP1(S) activates chaperone genes / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / Suppression of apoptosis / apical dendrite / beta-catenin destruction complex / tau-protein kinase / negative regulation of glucose import / Maturation of nucleoprotein / cellular response to interleukin-3 / negative regulation of TOR signaling / cellular response to glucocorticoid stimulus / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / positive regulation of protein targeting to mitochondrion / negative regulation of gene expression via chromosomal CpG island methylation / regulation of neuron projection development / G protein-coupled dopamine receptor signaling pathway / positive regulation of amyloid-beta formation / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / tau-protein kinase activity / glycogen metabolic process / cellular response to lithium ion / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / positive regulation of autophagy / extrinsic apoptotic signaling pathway / protein serine/threonine kinase binding / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of insulin receptor signaling pathway / excitatory postsynaptic potential / positive regulation of peptidyl-threonine phosphorylation / positive regulation of protein ubiquitination / peptidyl-threonine phosphorylation / negative regulation of canonical Wnt signaling pathway / tau protein binding / Wnt signaling pathway / positive regulation of protein catabolic process / cellular response to insulin stimulus / positive regulation of neuron apoptotic process / cell migration / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / nervous system development / postsynapse / peptidyl-serine phosphorylation / proteasome-mediated ubiquitin-dependent protein catabolic process / microtubule / viral protein processing / non-specific serine/threonine protein kinase / axon / protein phosphorylation / protein serine kinase activity / signaling receptor binding / protein serine/threonine kinase activity / neuronal cell body / positive regulation of gene expression / positive regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / cytoplasm / cytosol
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
Chem-D1E / Glycogen synthase kinase-3 alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsChodaparambil, J.V.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Chem Neurosci / Year: 2023
Title: Elucidation of the GSK3 alpha Structure Informs the Design of Novel, Paralog-Selective Inhibitors.
Authors: Amaral, B. / Capacci, A. / Anderson, T. / Tezer, C. / Bajrami, B. / Lulla, M. / Lucas, B. / Chodaparambil, J.V. / Marcotte, D. / Kumar, P.R. / Murugan, P. / Spilker, K. / Cullivan, M. / ...Authors: Amaral, B. / Capacci, A. / Anderson, T. / Tezer, C. / Bajrami, B. / Lulla, M. / Lucas, B. / Chodaparambil, J.V. / Marcotte, D. / Kumar, P.R. / Murugan, P. / Spilker, K. / Cullivan, M. / Wang, T. / Peterson, A.C. / Enyedy, I. / Ma, B. / Chen, T. / Yousaf, Z. / Calhoun, M. / Golonzhka, O. / Dillon, G.M. / Koirala, S.
History
DepositionNov 23, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 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 alpha
B: Axin peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,6503
Polymers41,1832
Non-polymers4671
Water48627
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-15 kcal/mol
Surface area16360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.881, 55.813, 66.807
Angle α, β, γ (deg.)90.000, 97.325, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Glycogen synthase kinase-3 alpha / GSK-3 alpha / Serine/threonine-protein kinase GSK3A


Mass: 39045.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P49840, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Protein/peptide Axin peptide


Mass: 2137.499 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-D1E / (4S,5R,8R)-4-ethyl-8-fluoro-4-[3-(3-fluoro-5-methoxypyridin-4-yl)phenyl]-7,7-dimethyl-4,5,6,7,8,9-hexahydro-2H-pyrazolo[3,4-b]quinolin-5-ol


Mass: 466.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / 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: 2.78 Å3/Da / Density % sol: 55.72 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: 0.2M calcium acetate, 0.1M BisTRIS pH 7.0, 5% Glycerol and 17% PEG3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.97 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.4→66.26 Å / Num. obs: 16932 / % possible obs: 96.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 57.5 Å2 / CC1/2: 0.99 / Net I/σ(I): 12.26
Reflection shellResolution: 2.4→2.48 Å / Num. unique obs: 1690 / CC1/2: 0.54

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5kpl

5kpl


Resolution: 2.4→66.26 Å / SU ML: 0.3015 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.8353
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2612 849 5.02 %
Rwork0.2315 16076 -
obs0.233 16925 96.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 72.9 Å2
Refinement stepCycle: LAST / Resolution: 2.4→66.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2714 0 34 27 2775
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00272826
X-RAY DIFFRACTIONf_angle_d0.89023865
X-RAY DIFFRACTIONf_chiral_restr0.1205441
X-RAY DIFFRACTIONf_plane_restr0.0047493
X-RAY DIFFRACTIONf_dihedral_angle_d5.8843390
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.550.32911430.30482693X-RAY DIFFRACTION98.27
2.55-2.750.32361430.28822670X-RAY DIFFRACTION98.25
2.75-3.020.32591450.26742747X-RAY DIFFRACTION98.87
3.02-3.460.29991190.27012501X-RAY DIFFRACTION90.44
3.46-4.360.26441470.20592718X-RAY DIFFRACTION98.52
4.36-66.260.21631520.21062747X-RAY DIFFRACTION96.92
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)
12.741814412511.029590998270.2989729694363.05349861845-1.505117525113.84786234639-0.3918510626281.986840972560.867388807979-0.5814944360240.233292832941-0.177557989695-0.6546765243851.189643886060.04633611049470.59278275699-0.1232869257650.02375965012461.445046494730.2273954413320.809296984316-3.79070009898-17.758604853517.5037842646
23.7330779652-0.3023584673110.6961359049331.73431771510.09063454309275.381754461810.04136002613320.3511550905590.0868386711647-0.0601075494845-0.108540544435-0.02561555846360.1039505644770.2807194386170.062311576760.38328435379-0.00794536015665-0.007044920661660.240550286945-0.004039180777460.420040922642-26.7272301333-25.983029001724.848125647
35.754062973360.169157513781-0.6549670027811.296798365691.721124081227.906739974340.1062312303141.26981389379-0.279712268248-0.345583893774-0.1564459909080.1373309868890.7528548687130.1600027661590.01079529757060.6846561788780.0550969650096-0.07759398419880.599717267335-0.1207143501970.5589985309-29.1589992097-36.348261699612.1099659756
49.31824499995-2.730063018172.450421140265.5686465968-1.21938422277.38954335150.049127685526-1.154175045942.171848353940.72413895786-0.199644636627-0.12311279157-1.24241760214-0.3005350702250.006966444047930.954299027012-0.1715174264710.2564127330640.623402443285-0.2734796510471.00101646316-36.6066626142-21.965036042745.1156525866
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 103 through 196 )AA103 - 1961 - 85
22chain 'A' and (resid 197 through 363 )AA197 - 36386 - 252
33chain 'A' and (resid 364 through 445 )AA364 - 445253 - 334
44chain 'B' and (resid 383 through 400 )BC383 - 4001 - 18

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