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- PDB-7sxh: BIO-8546 bound GSK3beta-axin complex -

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Basic information

Entry
Database: PDB / ID: 7sxh
TitleBIO-8546 bound GSK3beta-axin complex
Components
  • Glycogen synthase kinase-3 beta
  • axin peptide
KeywordsHYDROLASE / kinase
Function / homology
Function and homology information


regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium ...regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of dopaminergic neuron differentiation / positive regulation of protein localization to centrosome / maintenance of cell polarity / 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 / negative regulation of TOR signaling / 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 epithelial to mesenchymal transition / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / G protein-coupled dopamine receptor signaling pathway / regulation of axonogenesis / regulation of dendrite morphogenesis / tau-protein kinase activity / establishment of cell polarity / 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 / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / canonical Wnt signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / presynaptic modulation of chemical synaptic transmission / positive regulation of GTPase activity / positive regulation of protein export from nucleus / excitatory postsynaptic potential / negative regulation of cell migration / positive regulation of protein ubiquitination / hippocampus development / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / peptidyl-threonine phosphorylation / positive regulation of cell differentiation / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / positive regulation of protein-containing complex assembly / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / regulation of circadian rhythm / 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 / 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 protein binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / insulin receptor signaling pathway / kinase activity
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 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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: axin peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9313
Polymers41,4652
Non-polymers4671
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1250 Å2
ΔGint-15 kcal/mol
Surface area16270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.610, 72.640, 79.790
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 39553.359 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: Protein/peptide axin peptide


Mass: 1911.183 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.: 124 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.43 Å3/Da / Density % sol: 49.46 %
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 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.09→42.29 Å / Num. obs: 23943 / % possible obs: 99.3 % / Redundancy: 6.5 % / Biso Wilson estimate: 46.51 Å2 / CC1/2: 0.99 / Net I/σ(I): 14.65
Reflection shellResolution: 2.09→2.17 Å / Num. unique obs: 2242 / CC1/2: 0.6

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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: 2.09→42.29 Å / SU ML: 0.3169 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.3707
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2554 1196 5 %
Rwork0.2138 22722 -
obs0.2159 23918 99.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.64 Å2
Refinement stepCycle: LAST / Resolution: 2.09→42.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2773 0 34 124 2931
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00332897
X-RAY DIFFRACTIONf_angle_d0.96523969
X-RAY DIFFRACTIONf_chiral_restr0.1223454
X-RAY DIFFRACTIONf_plane_restr0.0054508
X-RAY DIFFRACTIONf_dihedral_angle_d6.2163409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.180.38581260.32612386X-RAY DIFFRACTION95.55
2.18-2.280.39251310.29122509X-RAY DIFFRACTION99.89
2.28-2.40.33251320.2742497X-RAY DIFFRACTION99.85
2.4-2.550.27281320.2552497X-RAY DIFFRACTION99.7
2.55-2.750.31571300.26152498X-RAY DIFFRACTION99.66
2.75-3.020.29831340.25072536X-RAY DIFFRACTION99.85
3.02-3.460.28471340.23422552X-RAY DIFFRACTION99.89
3.46-4.360.21141350.18112556X-RAY DIFFRACTION99.81
4.36-42.290.21571420.18052691X-RAY DIFFRACTION99.75
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)
12.94734220193-1.503735839514.499826045463.45033077418-0.8794421639488.73038866205-0.1152638438450.1700184922380.3421628296630.05318971794070.3706713953190.19494318425-0.3361720247150.286375197292-0.04025213337570.455848125883-0.0345374701337-0.02727137296570.587700960736-0.02628262692260.64464396565423.18331266958.3523033062517.6285769186
27.25197445519-1.02062122173-2.420731134642.11920518321-0.1453961666396.47789166445-0.4112904596790.238655768086-0.01678128814380.3186790144510.22615116825-0.4172869078940.2247793945920.2232576252420.08110548618160.442077172982-0.0311256152102-0.0318217950330.338806535226-0.04743606998380.4575519497316.2556941758.5288849489518.6937644806
38.668296641683.145754817784.097041689594.118890268533.93290673837.46854981575-0.0878654993992-0.1318620335660.0701294828248-0.114661760420.278155048174-0.46614618151-0.4445301398020.481225227218-0.2422475404860.3456289181740.00197976288056-0.02457484648790.3753472557350.007923708506840.40873006836817.01905257456.0307285668518.6464232155
42.923467299880.02298767121320.1443831001043.087800410692.205507057345.68700222515-0.0408485609140.3812169793070.324322551534-0.3697448568590.166363906014-0.174315975957-0.3476200001860.3925811453230.0271463561470.369030068658-0.04963911504680.01767772515940.3945287987150.04155295572970.4002333397325.11941244529-0.07745151451662.85408645872
54.212272826-0.845525835244-2.200209681742.952016264641.278724207768.495722769280.190426176866-0.6508728928460.7448030216250.171321998130.07136656318640.18275011274-0.8195176548-0.257311754938-0.2214800811070.6127092761040.01443009656420.0886792472490.530038195332-0.05455303163320.613983204872-3.086282206077.8017015103818.9157559861
65.31235762415-1.37971507686-1.565751586023.539618264510.7184009382763.343084734290.2355469188540.3627836281110.808646129622-0.23917011247-0.04319664101980.459018600775-0.569695008922-0.431326632014-0.2428408647310.4353941901870.0399317396610.006217869225420.4118967355930.08006261173950.6411924917-10.17658019997.487697745935.53896743598
77.1285358844-0.285606273607-1.093891609416.56408552321.232647967586.721255770140.01706703280470.03227081804520.7412118158120.324783781902-0.45399390851.3031985281-0.599509465325-1.63364129492-0.09800660725320.4551175429230.0766850266840.06322281152920.6723847843350.01460673747240.918936887353-24.64116113056.922504925219.35297441332
85.63897695577-1.505744851560.2206327274815.06798254738-0.4034405845956.54257743775-0.05821121245991.21059980692-0.0099135594896-0.397331866751-0.2538845893730.4576377120940.217240650693-0.778324812413-0.07233619259580.409452133469-0.033063857033-0.07769668754260.5904173390710.008627054565830.478483994985-11.5272196164-4.56409360241-4.52351641316
93.35978816265-1.44238841991-0.3306583759254.35547850836-0.2415859930474.08479794190.004916533414830.173918443085-0.431485331354-0.118616530632-0.1257898862970.00102697153850.7747911480740.3054209011170.1381796099720.541982244273-0.02442506942930.009390491985070.3564293903030.008123795557090.410738839872-0.205022597027-13.74082959465.44056059005
107.399514395861.61463167756.377605130526.1337135761-1.075338287638.87890476857-0.156986007763-0.3121473035081.87857817704-1.4903547534-0.403078842814-0.127805511593-2.03534561598-0.9892139100380.08307171493270.9613349986090.2382713921130.0337342780020.6793341371850.04326604230831.76380769041-23.431728612418.41276483286.34022665348
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 37 through 67 )AA37 - 671 - 31
22chain 'A' and (resid 68 through 103 )AA68 - 10332 - 67
33chain 'A' and (resid 104 through 133 )AA104 - 13368 - 94
44chain 'A' and (resid 134 through 198 )AA134 - 19895 - 157
55chain 'A' and (resid 199 through 219 )AA199 - 219158 - 178
66chain 'A' and (resid 220 through 273 )AA220 - 273179 - 232
77chain 'A' and (resid 274 through 300 )AA274 - 300233 - 258
88chain 'A' and (resid 301 through 320 )AA301 - 320259 - 278
99chain 'A' and (resid 321 through 383 )AA321 - 383279 - 341
1010chain 'B' and (resid 385 through 400 )BC385 - 4001 - 16

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