Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T70977 Target Info
Target Name Glycogen synthase kinase-3 beta (GSK-3B)
Synonyms Serine/threonine-protein kinase GSK3B; GSK-3 beta
Target Type Clinical trial Target
Gene Name GSK3B
Biochemical Class Kinase
UniProt ID
GSK3B_HUMAN
Ligand General Information  Top
Ligand Name Phosphonothreonine Ligand Info
Canonical SMILES CC(C(C(=O)O)N)OP(=O)(O)O
InChI 1S/C4H10NO6P/c1-2(3(5)4(6)7)11-12(8,9)10/h2-3H,5H2,1H3,(H,6,7)(H2,8,9,10)/t2-,3+/m1/s1
InChIKey USRGIUJOYOXOQJ-GBXIJSLDSA-N
PubChem Compound ID 3246323
Drug Binding Sites of Target  Top
PDB ID: 5HLP      X-RAY CRYSTAL STRUCTURE OF GSK3B IN COMPLEX WITH BRD3937
Method X-ray diffraction Resolution 2.45 Å Mutation No [1]
PDB Sequence
KVTTVVATPG
45
QGPDRPQEVS
55
YTDTKVIGNG
65
SFGVVYQAKL
75
CDSGELVAIK
85

KVLQDKRFKN
95
RELQIMRKLD
105
HCNIVRLRYF
115
FYSSEVYLNL
130
VLDYVPETVY
140

RVARHYSRAK
150
QTLPVIYVKL
160
YMYQLFRSLA
170
YIHSFGICHR
180
DIKPQNLLLD
190

PDTAVLKLCD
200
FGSAKQLVRG
210
EPNVSICSRY
221
YRAPELIFGA
231
TDYTSSIDVW
241

SAGCVLAELL
251
LGQPIFPGDS
261
GVDQLVEIIK
271
VLGTPREQIR
282
EMNPNFKFPQ
295

IKAHPWTKVF
305
RPRTPPEAIA
315
LCSRLLEYTP
325
TARLTPLEAC
335
AHSFFDELRD
345

PNVKLPNGRD
355
TPALFNFTTQ
365
ELSSNPPLAT
375
ILIPPHA
Residue
Distance (Å)
THR275
3.781
PRO276
1.372
ARG278
1.325
GLU279
3.226
Residue
Distance (Å)
GLN280
2.696
ILE281
3.019
THR324
4.851
PDB ID: 4NM5      Crystal structure of GSK-3/Axin complex bound to phosphorylated Wnt receptor LRP6 c-motif
Method X-ray diffraction Resolution 2.30 Å Mutation No [2]
PDB Sequence
GSMKVSRDKD
33
GSKVTTVVAT
43
PGQGPDRPQE
53
VSYTDTKVIG
63
NGSFGVVYQA
73

KLCDSGELVA
83
IKKVLQDKRF
93
KNRELQIMRK
103
LDHCNIVRLR
113
YFFYSSGEKK
123

DEVYLNLVLD
133
YVPETVYRVA
143
RHYSRAKQTL
153
PVIYVKLYMY
163
QLFRSLAYIH
173

SFGICHRDIK
183
PQNLLLDPDT
193
AVLKLCDFGS
203
AKQLVRGEPN
213
VSYICSRYYR
223

APELIFGATD
233
YTSSIDVWSA
243
GCVLAELLLG
253
QPIFPGDSGV
263
DQLVEIIKVL
273

GTPTREQIRE
283
MNPNYTEFKF
293
PQIKAHPWTK
303
VFRPRTPPEA
313
IALCSRLLEY
323

TPTARLTPLE
333
ACAHSFFDEL
343
RDPNVKLPNG
353
RDTPALFNFT
363
TQELSSNPPL
373

ATILIPPHAR
383
H
Residue
Distance (Å)
PHE93
3.774
LYS94
2.946
ARG96
2.837
ARG180
2.635
LYS205
2.558
Residue
Distance (Å)
PRO212
4.703
ASN213
3.291
VAL214
2.782
TYR234
4.369
PDB ID: 1O6L      Crystal structure of an activated Akt/protein kinase B (PKB-PIF chimera) ternary complex with AMP-PNP and GSK3 peptide
Method X-ray diffraction Resolution 1.60 Å Mutation No [3]
PDB Sequence
GRPRTTSFAE
12
Residue
Distance (Å)
GLU12
4.499
Residue
Distance (Å)
PDB ID: 1O6K      Structure of activated form of PKB kinase domain S474D with GSK3 peptide and AMP-PNP
Method X-ray diffraction Resolution 1.70 Å Mutation Yes [3]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
GLU12
4.342
Residue
Distance (Å)
PDB ID: 2JDO      STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CHLOROBENZYLOXY) ETHYLAMINO)ETHYL)AMIDE
Method X-ray diffraction Resolution 1.80 Å Mutation No [4]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.599
Residue
Distance (Å)
GLU12
4.103
PDB ID: 2X39      Structure of 4-Amino-N-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin- 4-yl)piperidine-4-carboxamide bound to PKB
Method X-ray diffraction Resolution 1.93 Å Mutation No [5]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.605
Residue
Distance (Å)
GLU12
4.000
PDB ID: 3CQW      Crystal Structure of Akt-1 complexed with substrate peptide and inhibitor
Method X-ray diffraction Resolution 2.00 Å Mutation Yes [6]
PDB Sequence
GRPRTTSFAE
10
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Residue
Distance (Å)
GLU10
4.115
Residue
Distance (Å)
PDB ID: 2UW9      STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH 4-(4-chloro-phenyl)-4-(4-(1H-pyrazol-4-yl)-phenyl)-piperidine
Method X-ray diffraction Resolution 2.10 Å Mutation No [7]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.784
Residue
Distance (Å)
GLU12
4.215
PDB ID: 3CQU      Crystal Structure of Akt-1 complexed with substrate peptide and inhibitor
Method X-ray diffraction Resolution 2.20 Å Mutation Yes [6]
PDB Sequence
GRPRTTSFAE
10
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Residue
Distance (Å)
GLU10
4.342
Residue
Distance (Å)
PDB ID: 2JDR      STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH THE INHIBITOR A-443654
Method X-ray diffraction Resolution 2.30 Å Mutation No [4]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.524
Residue
Distance (Å)
GLU12
4.329
PDB ID: 3E87      Crystal structures of the kinase domain of AKT2 in complex with ATP-competitive inhibitors
Method X-ray diffraction Resolution 2.30 Å Mutation Yes [8]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.787
Residue
Distance (Å)
GLU12
3.782
PDB ID: 3QKK      Spirochromane Akt Inhibitors
Method X-ray diffraction Resolution 2.30 Å Mutation Yes [9]
PDB Sequence
GRPRTTSFAE
10
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Residue
Distance (Å)
ALA9
4.609
Residue
Distance (Å)
GLU10
3.933
PDB ID: 3MV5      Crystal structure of Akt-1-inhibitor complexes
Method X-ray diffraction Resolution 2.47 Å Mutation Yes [10]
PDB Sequence
GRPRTTSFAE
10
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Residue
Distance (Å)
ALA9
4.571
Residue
Distance (Å)
GLU10
4.188
PDB ID: 3E88      Crystal structures of the kinase domain of AKT2 in complex with ATP-competitive inhibitors
Method X-ray diffraction Resolution 2.50 Å Mutation Yes [8]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.824
Residue
Distance (Å)
GLU12
3.642
PDB ID: 3OW4      Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors
Method X-ray diffraction Resolution 2.60 Å Mutation Yes [11]
PDB Sequence
GRPRTTSFAE
10
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Residue
Distance (Å)
GLU10
3.867
Residue
Distance (Å)
PDB ID: 3E8D      Crystal structures of the kinase domain of AKT2 in complex with ATP-competitive inhibitors
Method X-ray diffraction Resolution 2.70 Å Mutation Yes [8]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.701
Residue
Distance (Å)
GLU12
4.010
PDB ID: 2XH5      Structure of 4-(4-tert-Butylbenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4- yl)piperidin-4-amine bound to PKB
Method X-ray diffraction Resolution 2.72 Å Mutation Yes [5]
PDB Sequence
GRPRTTSFAE
12
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Residue
Distance (Å)
ALA11
4.821
Residue
Distance (Å)
GLU12
4.716
PDB ID: 4EKK      Akt1 with AMP-PNP
Method X-ray diffraction Resolution 2.80 Å Mutation Yes [12]
PDB Sequence
GRPRTTSFAE
10
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Residue
Distance (Å)
GLU10
3.467
Residue
Distance (Å)
References  Top
REF 1 Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects. ACS Chem Biol. 2016 Jul 15;11(7):1952-63.
REF 2 Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6. Elife. 2014 Mar 18;3:e01998.
REF 3 Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol. 2002 Dec;9(12):940-4.
REF 4 A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol. 2007 Mar 30;367(3):882-94.
REF 5 Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J Med Chem. 2010 Mar 11;53(5):2239-49.
REF 6 Synthesis and structure based optimization of novel Akt inhibitors. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3359-63.
REF 7 Identification of inhibitors of protein kinase B using fragment-based lead discovery. J Med Chem. 2007 May 17;50(10):2293-6.
REF 8 Aminofurazans as potent inhibitors of AKT kinase. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1508-11.
REF 9 Discovery and SAR of spirochromane Akt inhibitors. Bioorg Med Chem Lett. 2011 Apr 15;21(8):2410-4.
REF 10 Design of selective, ATP-competitive inhibitors of Akt. J Med Chem. 2010 Jun 24;53(12):4615-22.
REF 11 Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. Bioorg Med Chem Lett. 2010 Dec 1;20(23):7037-41.
REF 12 An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci Signal. 2012 May 8;5(223):ra37.

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