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PDBsum entry 1i09

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1i09
Jmol
Contents
Protein chain
338 a.a. *
Ligands
PO4 ×4
Waters ×46
* Residue conservation analysis
PDB id:
1i09
Name: Transferase
Title: Structure of glycogen synthase kinase-3 (gsk3b)
Structure: Glycogen synthase kinase-3 beta. Chain: a, b. Synonym: gsk-3 beta, gsk3b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469
Biol. unit: Dimer (from PQS)
Resolution:
2.70Å     R-factor:   0.242     R-free:   0.274
Authors: E.Ter Haar,J.T.Coll,J.Jain
Key ref:
E.ter Haar et al. (2001). Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol, 8, 593-596. PubMed id: 11427888 DOI: 10.1038/89624
Date:
29-Jan-01     Release date:   01-Jan-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P49841  (GSK3B_HUMAN) -  Glycogen synthase kinase-3 beta
Seq:
Struc:
420 a.a.
338 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
   Enzyme class 2: E.C.2.7.11.26  - [Tau protein] kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [tau protein] = ADP + [tau protein] phosphate
ATP
+ [tau protein]
= ADP
+ [tau protein] phosphate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cell body   17 terms 
  Biological process     protein localization to microtubule   72 terms 
  Biochemical function     RNA polymerase II transcription factor binding     19 terms  

 

 
    reference    
 
 
DOI no: 10.1038/89624 Nat Struct Biol 8:593-596 (2001)
PubMed id: 11427888  
 
 
Structure of GSK3beta reveals a primed phosphorylation mechanism.
E.ter Haar, J.T.Coll, D.A.Austen, H.M.Hsiao, L.Swenson, J.Jain.
 
  ABSTRACT  
 
GSK3beta was identified as the kinase that phosphorylates glycogen synthase but is now known to be involved in multiple signaling pathways. GSK3beta prefers prior phosphorylation of its substrates. We present the structure of unphosphorylated GSK3beta at 2.7 A. The orientation of the two domains and positioning of the activation loop of GSK3beta are similar to those observed in activated kinases. A phosphate ion held by Arg 96, Arg 180 and Lys 205 occupies the same position as the phosphate group of the phosphothreonine in activated p38gamma, CDK2 or ERK2. A loop from a neighboring molecule in the crystal occupies a portion of the substrate binding groove. The structure explains the unique primed phosphorylation mechanism of GSK3beta and how GSK3beta relies on a phosphoserine in the substrate for the alignment of the beta- and alpha-helical domains.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Representative portion of a 2F[o] - F[c] electron density map contoured at 1.5 .
Figure 4.
Figure 4. The GSK3 substrate binding groove.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 593-596) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21354422 A.Licht-Murava, B.Plotkin, M.Eisenstein, and H.Eldar-Finkelman (2011).
Elucidating substrate and inhibitor binding sites on the surface of GSK-3β and the refinement of a competitive inhibitor.
  J Mol Biol, 408, 366-378.  
20473698 H.Sun, Y.J.Jiang, Q.S.Yu, C.C.Luo, and J.W.Zou (2011).
The effect of Li(+) on GSK-3 inhibition: Molecular dynamics simulation.
  J Mol Model, 17, 377-381.  
21443429 J.L.Johnson, S.G.Rupasinghe, F.Stefani, M.A.Schuler, and E.Gonzalez de Mejia (2011).
Citrus flavonoids luteolin, apigenin, and quercetin inhibit glycogen synthase kinase-3β enzymatic activity by lowering the interaction energy within the binding cavity.
  J Med Food, 14, 325-333.  
21212533 K.Saeki, M.Machida, Y.Kinoshita, R.Takasawa, and S.Tanuma (2011).
Glycogen synthase kinase-3β2 has lower phosphorylation activity to tau than glycogen synthase kinase-3β1.
  Biol Pharm Bull, 34, 146-149.  
21486568 W.Berrabah, P.Aumercier, P.Lefebvre, and B.Staels (2011).
Control of nuclear receptor activities in metabolism by post-translational modifications.
  FEBS Lett, 585, 1640-1650.  
21105670 I.Buch, D.Fishelovitch, N.London, B.Raveh, H.J.Wolfson, and R.Nussinov (2010).
Allosteric regulation of glycogen synthase kinase 3β: a theoretical study.
  Biochemistry, 49, 10890-10901.  
20420491 J.Avila, F.Wandosell, and F.Hernández (2010).
Role of glycogen synthase kinase-3 in Alzheimer's disease pathogenesis and glycogen synthase kinase-3 inhibitors.
  Expert Rev Neurother, 10, 703-710.  
20080974 J.L.Buescher, and C.J.Phiel (2010).
A noncatalytic domain of glycogen synthase kinase-3 (GSK-3) is essential for activity.
  J Biol Chem, 285, 7957-7963.  
  20631880 R.Ko, H.D.Jang, and S.Y.Lee (2010).
GSK3beta Inhibitor Peptide Protects Mice from LPS-induced Endotoxin Shock.
  Immune Netw, 10, 99.  
20043192 S.L.Howng, C.C.Hwang, C.Y.Hsu, M.Y.Hsu, C.Y.Teng, C.H.Chou, M.F.Lee, C.H.Wu, S.J.Chiou, A.S.Lieu, J.K.Loh, C.N.Yang, C.S.Lin, and Y.R.Hong (2010).
Involvement of the residues of GSKIP, AxinGID, and FRATtide in their binding with GSK3beta to unravel a novel C-terminal scaffold-binding region.
  Mol Cell Biochem, 339, 23-33.  
19366350 G.V.Rayasam, V.K.Tulasi, R.Sodhi, J.A.Davis, and A.Ray (2009).
Glycogen synthase kinase 3: more than a namesake.
  Br J Pharmacol, 156, 885-898.  
19440740 K.H.Kim, I.Gaisina, F.Gallier, D.Holzle, S.Y.Blond, A.Mesecar, and A.P.Kozikowski (2009).
Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors.
  J Mol Model, 15, 1463-1479.  
19003984 N.Zhang, Y.Jiang, J.Zou, Q.Yu, and W.Zhao (2009).
Structural basis for the complete loss of GSK3beta catalytic activity due to R96 mutation investigated by molecular dynamics study.
  Proteins, 75, 671-681.  
19006085 P.Goñi-Oliver, J.Avila, and F.Hernández (2009).
Calpain-mediated truncation of GSK-3 in post-mortem brain samples.
  J Neurosci Res, 87, 1156-1161.  
18839067 S.Prasanna, P.R.Daga, A.Xie, and R.J.Doerksen (2009).
Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking.
  J Comput Aided Mol Des, 23, 113-127.  
18851699 A.Kannoji, S.Phukan, V.Sudher Babu, and V.N.Balaji (2008).
GSK3beta: a master switch and a promising target.
  Expert Opin Ther Targets, 12, 1443-1455.  
18184370 D.Muyllaert, A.Kremer, T.Jaworski, P.Borghgraef, H.Devijver, S.Croes, I.Dewachter, and F.Van Leuven (2008).
Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology?
  Genes Brain Behav, 7, 57-66.  
18342604 J.C.Ngo, K.Giang, S.Chakrabarti, C.T.Ma, N.Huynh, J.C.Hagopian, P.C.Dorrestein, X.D.Fu, J.A.Adams, and G.Ghosh (2008).
A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1.
  Mol Cell, 29, 563-576.
PDB code: 3beg
18816110 K.Vougogiannopoulou, Y.Ferandin, K.Bettayeb, V.Myrianthopoulos, O.Lozach, Y.Fan, C.H.Johnson, P.Magiatis, A.L.Skaltsounis, E.Mikros, and L.Meijer (2008).
Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.
  J Med Chem, 51, 6421-6431.  
18436524 S.Braconi Quintaje, and S.Orchard (2008).
The annotation of both human and mouse kinomes in UniProtKB/Swiss-Prot: one small step in manual annotation, one giant leap for full comprehension of genomes.
  Mol Cell Proteomics, 7, 1409-1419.  
17240048 G.M.Cheetham, P.A.Charlton, J.M.Golec, and J.R.Pollard (2007).
Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680.
  Cancer Lett, 251, 323-329.  
17997701 J.Avila, and F.Hernández (2007).
GSK-3 inhibitors for Alzheimer's disease.
  Expert Rev Neurother, 7, 1527-1533.  
17560826 K.A.Burns, and J.P.Vanden Heuvel (2007).
Modulation of PPAR activity via phosphorylation.
  Biochim Biophys Acta, 1771, 952-960.  
17224784 L.Dugo, M.Collin, and C.Thiemermann (2007).
Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation.
  Shock, 27, 113-123.  
17179144 M.Wrzaczek, W.Rozhon, and C.Jonak (2007).
A Proteasome-regulated glycogen synthase kinase-3 modulates disease response in plants.
  J Biol Chem, 282, 5249-5255.  
17569662 P.Goñi-Oliver, J.J.Lucas, J.Avila, and F.Hernández (2007).
N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation.
  J Biol Chem, 282, 22406-22413.  
17644338 P.Patwardhan, and W.T.Miller (2007).
Processive phosphorylation: mechanism and biological importance.
  Cell Signal, 19, 2218-2226.  
17179138 R.Kalamegham, D.Sturgill, E.Siegfried, and B.Oliver (2007).
Drosophila mojoless, a retroposed GSK-3, has functionally diverged to acquire an essential role in male fertility.
  Mol Biol Evol, 24, 732-742.  
17188038 P.A.Lochhead, R.Kinstrie, G.Sibbet, T.Rawjee, N.Morrice, and V.Cleghon (2006).
A chaperone-dependent GSK3beta transitional intermediate mediates activation-loop autophosphorylation.
  Mol Cell, 24, 627-633.  
16893889 R.Ilouz, N.Kowalsman, M.Eisenstein, and H.Eldar-Finkelman (2006).
Identification of novel glycogen synthase kinase-3beta substrate-interacting residues suggests a common mechanism for substrate recognition.
  J Biol Chem, 281, 30621-30630.  
16732330 S.Benzeno, F.Lu, M.Guo, O.Barbash, F.Zhang, J.G.Herman, P.S.Klein, A.Rustgi, and J.A.Diehl (2006).
Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1.
  Oncogene, 25, 6291-6303.  
15741170 D.Komander, G.Kular, M.Deak, D.R.Alessi, and D.M.van Aalten (2005).
Role of T-loop phosphorylation in PDK1 activation, stability, and substrate binding.
  J Biol Chem, 280, 18797-18802.
PDB code: 2biy
15780591 J.R.Woodgett (2005).
Recent advances in the protein kinase B signaling pathway.
  Curr Opin Cell Biol, 17, 150-157.  
15657054 M.D.Jacobs, J.Black, O.Futer, L.Swenson, B.Hare, M.Fleming, and K.Saxena (2005).
Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002.
  J Biol Chem, 280, 13728-13734.
PDB codes: 1yhs 1yi3 1yi4
15326593 A.M.Aronov, and G.W.Bemis (2004).
A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors.
  Proteins, 57, 36-50.  
14593110 A.V.Skurat, and A.D.Dietrich (2004).
Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases.
  J Biol Chem, 279, 2490-2498.  
15143183 D.Papadopoulou, M.W.Bianchi, and M.Bourouis (2004).
Functional studies of shaggy/glycogen synthase kinase 3 phosphorylation sites in Drosophila melanogaster.
  Mol Cell Biol, 24, 4909-4919.  
15456871 L.Litovchick, A.Chestukhin, and J.A.DeCaprio (2004).
Glycogen synthase kinase 3 phosphorylates RBL2/p130 during quiescence.
  Mol Cell Biol, 24, 8970-8980.  
14960716 L.M.Iakoucheva, P.Radivojac, C.J.Brown, T.R.O'Connor, J.G.Sikes, Z.Obradovic, and A.K.Dunker (2004).
The importance of intrinsic disorder for protein phosphorylation.
  Nucleic Acids Res, 32, 1037-1049.  
15273306 N.Kannan, and A.F.Neuwald (2004).
Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2alpha.
  Protein Sci, 13, 2059-2077.  
15073180 R.van Amerongen, H.van der Gulden, F.Bleeker, J.Jonkers, and A.Berns (2004).
Characterization and functional analysis of the murine Frat2 gene.
  J Biol Chem, 279, 26967-26974.  
14985354 T.R.Salas, J.Kim, F.Vakar-Lopez, A.L.Sabichi, P.Troncoso, G.Jenster, A.Kikuchi, S.Y.Chen, L.Shemshedini, M.Suraokar, C.J.Logothetis, J.DiGiovanni, S.M.Lippman, and D.G.Menter (2004).
Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity.
  J Biol Chem, 279, 19191-19200.  
12615961 B.W.Doble, and J.R.Woodgett (2003).
GSK-3: tricks of the trade for a multi-tasking kinase.
  J Cell Sci, 116, 1175-1186.  
12796505 F.Zhang, C.J.Phiel, L.Spece, N.Gurvich, and P.S.Klein (2003).
Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3.
  J Biol Chem, 278, 33067-33077.  
12409305 J.H.Cho, and G.V.Johnson (2003).
Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding.
  J Biol Chem, 278, 187-193.  
14690613 K.Stankunas, J.H.Bayle, J.E.Gestwicki, Y.M.Lin, T.J.Wandless, and G.R.Crabtree (2003).
Conditional protein alleles using knockin mice and a chemical inducer of dimerization.
  Mol Cell, 12, 1615-1624.  
14700633 L.Meijer, A.L.Skaltsounis, P.Magiatis, P.Polychronopoulos, M.Knockaert, M.Leost, X.P.Ryan, C.A.Vonica, A.Brivanlou, R.Dajani, C.Crovace, C.Tarricone, A.Musacchio, S.M.Roe, L.Pearl, and P.Greengard (2003).
GSK-3-selective inhibitors derived from Tyrian purple indirubins.
  Chem Biol, 10, 1255-1266.
PDB code: 1uv5
14563837 M.A.Gregory, Y.Qi, and S.R.Hann (2003).
Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization.
  J Biol Chem, 278, 51606-51612.  
14536078 M.Welcker, J.Singer, K.R.Loeb, J.Grim, A.Bloecher, M.Gurien-West, B.E.Clurman, and J.M.Roberts (2003).
Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation.
  Mol Cell, 12, 381-392.  
12925738 O.Marin, V.H.Bustos, L.Cesaro, F.Meggio, M.A.Pagano, M.Antonelli, C.C.Allende, L.A.Pinna, and J.E.Allende (2003).
A noncanonical sequence phosphorylated by casein kinase 1 in beta-catenin may play a role in casein kinase 1 targeting of important signaling proteins.
  Proc Natl Acad Sci U S A, 100, 10193-10200.  
14700620 P.M.Fischer (2003).
CDK versus GSK-3 inhibition: a purple haze no longer?
  Chem Biol, 10, 1144-1146.  
12900420 T.R.Salas, S.A.Reddy, J.L.Clifford, R.J.Davis, A.Kikuchi, S.M.Lippman, and D.G.Menter (2003).
Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei.
  J Biol Chem, 278, 41338-41346.  
12111750 A.Martinez, A.Castro, I.Dorronsoro, and M.Alonso (2002).
Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation.
  Med Res Rev, 22, 373-384.  
12110242 B.Haefner (2002).
NF-kappa B: arresting a major culprit in cancer.
  Drug Discov Today, 7, 653-663.  
12399181 C.Jonak, and H.Hirt (2002).
Glycogen synthase kinase 3/SHAGGY-like kinases in plants: an emerging family with novel functions.
  Trends Plant Sci, 7, 457-461.  
11955436 C.Liu, Y.Li, M.Semenov, C.Han, G.H.Baeg, Y.Tan, Z.Zhang, X.Lin, and X.He (2002).
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
  Cell, 108, 837-847.  
12351631 C.M.Sheridan, E.K.Heist, C.R.Beals, G.R.Crabtree, and P.Gardner (2002).
Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3.
  J Biol Chem, 277, 48664-48676.  
11861647 D.M.Ferkey, and D.Kimelman (2002).
Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin.
  J Biol Chem, 277, 16147-16152.  
12419241 D.P.Brazil, J.Park, and B.A.Hemmings (2002).
PKB binding proteins. Getting in on the Akt.
  Cell, 111, 293-303.  
12065620 F.Mukai, K.Ishiguro, Y.Sano, and S.C.Fujita (2002).
Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta.
  J Neurochem, 81, 1073-1083.  
12237287 G.M.Cheetham, R.M.Knegtel, J.T.Coll, S.B.Renwick, L.Swenson, P.Weber, J.A.Lippke, and D.A.Austen (2002).
Crystal structure of aurora-2, an oncogenic serine/threonine kinase.
  J Biol Chem, 277, 42419-42422.
PDB code: 1muo
11879773 H.Eldar-Finkelman (2002).
Glycogen synthase kinase 3: an emerging therapeutic target.
  Trends Mol Med, 8, 126-132.  
12387679 O.Kaidanovich, and H.Eldar-Finkelman (2002).
The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes.
  Expert Opin Ther Targets, 6, 555-561.  
11805297 S.C.h.Papasozomenos, and A.Shanavas (2002).
Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer's disease.
  Proc Natl Acad Sci U S A, 99, 1140-1145.  
11967263 T.Hagen, E.Di Daniel, A.A.Culbert, and A.D.Reith (2002).
Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells.
  J Biol Chem, 277, 23330-23335.  
11879670 V.Stambolic (2002).
PTEN: a new twist on beta-catenin?
  Trends Pharmacol Sci, 23, 104-106.  
11439177 A.J.Harwood (2001).
Regulation of GSK-3: a cellular multiprocessor.
  Cell, 105, 821-824.  
11590039 D.Gurwitz, and H.Eldar-Finkelman (2001).
Monitor and Molecules.
  Drug Discov Today, 6, 1072-1073.  
11589691 P.Cohen (2001).
The role of protein phosphorylation in human health and disease. The Sir Hans Krebs Medal Lecture.
  Eur J Biochem, 268, 5001-5010.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.