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- PDB-4j1r: Crystal Structure of GSK3b in complex with inhibitor 15R -

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Basic information

Entry
Database: PDB / ID: 4j1r
TitleCrystal Structure of GSK3b in complex with inhibitor 15R
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / Structural Genomics / PSI-Biology / New York Structural Genomics Research Consortium / NYSGRC / Kinase / Phosphorylation
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 / 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 TORC2 signaling / beta-arrestin-dependent dopamine receptor signaling pathway ...negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 TORC2 signaling / beta-arrestin-dependent dopamine receptor signaling pathway / negative regulation of dopaminergic neuron differentiation / positive regulation of protein localization to centrosome / maintenance of cell polarity / positive regulation of cilium assembly / CRMPs in Sema3A signaling / tau-protein kinase / heart valve development / beta-catenin destruction complex / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / regulation of protein export from nucleus / cellular response to interleukin-3 / Maturation of nucleoprotein / 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 / regulation of long-term synaptic potentiation / Wnt signalosome / negative regulation of TOR signaling / regulation of microtubule-based process / AKT phosphorylates targets in the cytosol / Disassembly of the destruction complex and recruitment of AXIN to the membrane / positive regulation of protein binding / regulation of axon extension / negative regulation of calcineurin-NFAT signaling cascade / Maturation of nucleoprotein / negative regulation of protein localization to nucleus / negative regulation of epithelial to mesenchymal transition / tau-protein kinase activity / positive regulation of cell-matrix adhesion / glycogen metabolic process / ER overload response / regulation of axonogenesis / regulation of dendrite morphogenesis / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / establishment of cell polarity / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / canonical Wnt signaling pathway / negative regulation of osteoblast differentiation / NF-kappaB binding / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of protein-containing complex assembly / regulation of cellular response to heat / extrinsic apoptotic signaling pathway / cellular response to retinoic acid / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of type I interferon production / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / response to endoplasmic reticulum stress / negative regulation of cell migration / positive regulation of protein export from nucleus / presynaptic modulation of chemical synaptic transmission / positive regulation of protein ubiquitination / peptidyl-serine phosphorylation / regulation of microtubule cytoskeleton organization / hippocampus development / positive regulation of cell differentiation / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / positive regulation of protein-containing complex assembly / excitatory postsynaptic potential / negative regulation of canonical Wnt signaling pathway / circadian rhythm / regulation of circadian rhythm / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / B-WICH complex positively regulates rRNA expression / beta-catenin binding / Degradation of beta-catenin by the destruction complex / tau protein binding / cellular response to amyloid-beta / Wnt signaling pathway / neuron projection development / kinase activity / p53 binding / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / insulin receptor signaling pathway / protein autophosphorylation
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-I5R / : / PHOSPHATE ION / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.702 Å
AuthorsZhan, C. / Wang, Y. / Wach, J. / Sheehan, P. / Zhong, C. / Harris, R. / Patskovsky, Y. / Bishop, J. / Haggarty, S. / Ramek, A. ...Zhan, C. / Wang, Y. / Wach, J. / Sheehan, P. / Zhong, C. / Harris, R. / Patskovsky, Y. / Bishop, J. / Haggarty, S. / Ramek, A. / Berry, K. / O'Herin, C. / Koehler, A.N. / Hung, A.W. / Young, D.W. / Almo, S.C. / New York Structural Genomics Research Consortium (NYSGRC)
CitationJournal: To be Published
Title: Fragment-based approach using diversity-oriented synthesis yields a GSK3b inhibitor
Authors: Wang, Y. / Wach, J. / Sheehan, P. / Zhong, C. / Zhan, C. / Harris, R. / Almo, S.C. / Bishop, J. / Haggarty, S. / Ramek, A. / Berry, K. / O'Herin, C. / Koehler, A.N. / Hung, A.W. / Young, D.W.
History
DepositionFeb 1, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
C: Glycogen synthase kinase-3 beta
D: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,36716
Polymers188,7184
Non-polymers1,65012
Water1,71195
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5924
Polymers47,1791
Non-polymers4123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5924
Polymers47,1791
Non-polymers4123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5924
Polymers47,1791
Non-polymers4123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5924
Polymers47,1791
Non-polymers4123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: Glycogen synthase kinase-3 beta
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,1848
Polymers94,3592
Non-polymers8256
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2460 Å2
ΔGint-21 kcal/mol
Surface area31910 Å2
MethodPISA
6
C: Glycogen synthase kinase-3 beta
D: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,1848
Polymers94,3592
Non-polymers8256
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2590 Å2
ΔGint-22 kcal/mol
Surface area32200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.516, 67.441, 116.422
Angle α, β, γ (deg.)90.130, 90.080, 81.110
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11chain A and (resseq 36:119 or resseq 126:215 or resseq 217:383 )
21chain B and (resseq 36:119 or resseq 126:215 or resseq 217:286 or resseq 289:383 )
31chain C and (resseq 36:119 or resseq 126:215 or resseq 217:383 )
41chain D and (resseq 36:119 or resseq 126:215 or resseq 217:383 )

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSSERSERchain 'A' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )AA36 - 11940 - 123
12VALVALSERSERchain 'A' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )AA126 - 215130 - 219
13ILEILEARGARGchain 'A' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )AA217 - 383221 - 387
21LYSLYSSERSERchain 'B' and (resseq 36:119 or resseq 126:215 or resseq 217:286 or resseq 289:383 )BB36 - 11940 - 123
22VALVALSERSERchain 'B' and (resseq 36:119 or resseq 126:215 or resseq 217:286 or resseq 289:383 )BB126 - 215130 - 219
23ILEILEPROPROchain 'B' and (resseq 36:119 or resseq 126:215 or resseq 217:286 or resseq 289:383 )BB217 - 286221 - 290
24THRTHRARGARGchain 'B' and (resseq 36:119 or resseq 126:215 or resseq 217:286 or resseq 289:383 )BB289 - 383293 - 387
31LYSLYSSERSERchain 'C' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )CC36 - 11940 - 123
32VALVALSERSERchain 'C' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )CC126 - 215130 - 219
33ILEILEARGARGchain 'C' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )CC217 - 383221 - 387
41LYSLYSSERSERchain 'D' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )DD36 - 11940 - 123
42VALVALSERSERchain 'D' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )DD126 - 215130 - 219
43ILEILEARGARGchain 'D' and (resseq 36:119 or resseq 126:215 or resseq 217:383 )DD217 - 383221 - 387

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Components

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


Mass: 47179.484 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): High five cell
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#3: Chemical
ChemComp-I5R / (2R)-2-(1H-indol-3-ylmethyl)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one


Mass: 278.309 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H14N4O
#4: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O
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: 2.78 Å3/Da / Density % sol: 55.68 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 9.2
Details: 20% PEG-3350, 0.2M dipotassium phosphate, pH 9.2, VAPOR DIFFUSION, SITTING DROP, temperature 290.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 6, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
Reflection twinOperator: k,h,-l / Fraction: 0.469
ReflectionResolution: 2.7→50 Å / Num. obs: 54028 / % possible obs: 98 % / Redundancy: 2.1 % / Rmerge(I) obs: 0.097 / Χ2: 1.126 / Net I/σ(I): 7.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.7-2.752.20.86826280.984196.9
2.75-2.82.20.76727081.003196.9
2.8-2.852.20.72126911.03197.4
2.85-2.912.20.59427211197.8
2.91-2.972.10.44226221.116197.6
2.97-3.042.10.38127331.072197.4
3.04-3.122.20.32526631.129197.8
3.12-3.22.20.26527561.189197.8
3.2-3.32.20.20826401.129197.9
3.3-3.42.10.16426941.216197.9
3.4-3.522.20.13727331.228197.7
3.52-3.662.10.11426571.299198.2
3.66-3.832.20.09227261.257197.7
3.83-4.032.10.07927101.257198.3
4.03-4.292.10.06527031.111198
4.29-4.622.10.05426961.11198.2
4.62-5.082.10.05127141.101198.4
5.08-5.812.10.05427461.169199.2
5.81-7.322.20.04827561.101199.4
7.32-502.20.03227311.026199.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIX1.7.3_928refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1GNG

1gng


Resolution: 2.702→46.963 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8804 / σ(F): 1.96 / Phase error: 19.41 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflectionSelection details
Rfree0.1932 2825 5.23 %RANDOM
Rwork0.173 ---
obs0.1745 54014 97.21 %-
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 33.375 Å2 / ksol: 0.333 e/Å3
Displacement parametersBiso max: 158.3 Å2 / Biso mean: 64.0647 Å2 / Biso min: 10.15 Å2
Baniso -1Baniso -2Baniso -3
1--5.7024 Å2-2.0829 Å20.0477 Å2
2---7.9053 Å20.1095 Å2
3---13.6078 Å2
Refinement stepCycle: LAST / Resolution: 2.702→46.963 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11045 0 108 95 11248
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01411441
X-RAY DIFFRACTIONf_angle_d1.3615590
X-RAY DIFFRACTIONf_chiral_restr0.0781742
X-RAY DIFFRACTIONf_plane_restr0.0061996
X-RAY DIFFRACTIONf_dihedral_angle_d12.664271
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDTypeRms dev position (Å)
11A2696X-RAY DIFFRACTIONPOSITIONAL0.146
12B2696X-RAY DIFFRACTIONPOSITIONAL0.146
13C2711X-RAY DIFFRACTIONPOSITIONAL0.102
14D2713X-RAY DIFFRACTIONPOSITIONAL0.114
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7016-2.74820.30731410.27942113225477
2.7482-2.79810.30651120.27472546265893
2.7981-2.85190.30541390.28792585272492
2.8519-2.91010.28551400.26252572271292
2.9101-2.97340.2521340.25112532266693
2.9734-3.04260.23861500.24852605275592
3.0426-3.11860.26611200.24222576269693
3.1186-3.20290.26441230.22312641276494
3.2029-3.29720.23511570.20912514267192
3.2972-3.40360.23361280.20012598272693
3.4036-3.52520.23081420.18372606274893
3.5252-3.66630.21551340.17542571270593
3.6663-3.8330.18241290.16422599272893
3.833-4.0350.17761540.15462566272093
4.035-4.28770.15661270.13522583271093
4.2877-4.61850.13461450.12152592273793
4.6185-5.08270.14321410.13192606274793
5.0827-5.81710.16911520.16412604275694
5.8171-7.32440.16541340.15892650278495
7.3244-46.97010.15521540.13582599275394

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