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Glycogen synthase kinase 3

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<StructureSection load='' size='450' side='right' scene='Journal:JBIC:2/Opening/1' caption='Crystal Structure of Glycogen Synthase Kinase 3ß bound to Anticancer Ruthenium Complex (PDB code [[3m1s]])'>
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<StructureSection load='' size='350' side='right' scene='Journal:JBIC:2/Opening/1' caption='Crystal Structure of Glycogen Synthase Kinase 3ß bound to Anticancer Ruthenium Complex (PDB code [[3m1s]])'>
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'''Glycogen synthase kinase 3''' (GSK-3) is a serine/threonine protein kinase. GSK-3 is active in a number of intracellular signaling pathways. GSK-3 regulates glycogen synthase as well as other proteins. GSK-3 inhibition is studied as a therapeutic target in diseases like Alzheimer, diabetes, bipolar disorder and some cancers. For more details see [[Student Project 9 for UMass Chemistry 423 Spring 2015]].
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== Function ==
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'''Glycogen synthase kinase 3''' (GSK-3) is a serine/threonine protein kinase. GSK-3 is active in a number of intracellular signaling pathways. GSK-3 regulates glycogen synthase as well as other proteins<ref>PMID:17530463</ref>. For more details see [[Student Project 9 for UMass Chemistry 423 Spring 2015]].
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'''Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref>'''
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== Relevance ==
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GSK-3 inhibition is studied as a therapeutic target in diseases like Alzheimer, diabetes, bipolar disorder and some cancers<ref>PMID:17100582</ref>.
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== Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref> ==
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;A crystal structure of an <scene name='Journal:JBIC:2/Half_sandwich_complex_no_bonds/1'>organometallic half-sandwich ruthenium complex </scene>bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals that the inhibitor binds to the <scene name='Journal:JBIC:2/Atp_binding_site2/2'>ATP binding site</scene> via an induced fit mechanism utlizing several <scene name='Journal:JBIC:2/Half_sandwich_complex/3'>hydrogen bonds</scene> and <scene name='Journal:JBIC:2/Half_sandwich_hydrophobic_stic/1'>hydrophobic interactions</scene>. Importantly, the metal is not involved in any direct interaction with the protein kinase but fulfills a purely structural role. The unique, bulky molecular structure of the half-sandwich complex with the CO-ligand oriented perpendicular to the pyridocarbazole heterocycle allows the complex to stretch the whole distance <scene name='Journal:JBIC:2/Half_sandwich_hydrophobic/5'>sandwiched between the faces of the N- and C-terminal lobes</scene> and to interact tightly with <scene name='Journal:JBIC:2/Glycine_rich_loop2/4'>the flexible glycine-rich loop</scene>. Although this complex is a conventional ATP-competitive binder, the unique shape of the complex allows novel interactions with the glycine-rich loop which are crucial for binding potency and selectivity. It can be hypothesized that coordination spheres which present other ligands towards the glycine-rich loop might display completely different protein kinase selectivities.
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;A crystal structure of an <scene name='Journal:JBIC:2/Half_sandwich_complex_no_bonds/1'>organometallic half-sandwich ruthenium complex </scene>bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals that the inhibitor binds to the <scene name='Journal:JBIC:2/Atp_binding_site2/2'>ATP binding site</scene> via an induced fit mechanism utlizing several <scene name='Journal:JBIC:2/Half_sandwich_complex/3'>hydrogen bonds</scene> and <scene name='Journal:JBIC:2/Half_sandwich_hydrophobic_stic/1'>hydrophobic interactions</scene>. Importantly, the metal is not involved in any direct interaction with the protein kinase but fulfills a purely structural role. The unique, bulky molecular structure of the half-sandwich complex with the CO-ligand oriented perpendicular to the pyridocarbazole heterocycle allows the complex to stretch the whole distance <scene name='Journal:JBIC:2/Half_sandwich_hydrophobic/5'>sandwiched between the faces of the N- and C-terminal lobes</scene> and to interact tightly with <scene name='Journal:JBIC:2/Glycine_rich_loop2/4'>the flexible glycine-rich loop</scene>. Although this complex is a conventional ATP-competitive binder, the unique shape of the complex allows novel interactions with the glycine-rich loop which are crucial for binding potency and selectivity. It can be hypothesized that coordination spheres which present other ligands towards the glycine-rich loop might display completely different protein kinase selectivities.
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</StructureSection>
 
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__NOTOC__
 
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===3D structures of glycogen synthase kinase 3===
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==3D structures of glycogen synthase kinase 3==
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[[Glycogen synthase kinase 3 3D structures]]
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
 
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{{#tree:id=OrganizedByTopic|openlevels=0|
 
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*GSK-3
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</StructureSection>
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**[[1i09]], [[1h8f]] – hGSK-3 β – human<br />
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**[[4e7w]] – GSK-3 (mutant) – smut fungus<br />
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*GSK-3 binary complex
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**[[1gng]] - hGSK-3 β + Frattide peptide<br />
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**[[1q4l]], [[1uv5]], [[1q5k]], [[1r0e]], [[2o5k]], [[2ow3]], [[3du8]], [[3f7z]], [[3f88]], [[3i4b]], [[3gb2]], [[3l1s]], [[3q3b]], [[3zrk]], [[3zrl]], [[3zrm]], [[3sd0]], [[4dit]], [[4afj]], [[4acc]], [[4acd]], [[4acg]], [[4ach]], [[3say]], [[4iq6]], [[4j1r]], [[4j71]] - hGSK-3 β + inhibitor<br />
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**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />
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**[[1j1c]] - hGSK-3 β + ADP<br />
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**[[1q3d]], [[1q3w]], [[1q41]] - hGSK-3 β + ATP-mimetic inhibitor<br />
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**[[4ptc]], [[4pte]], [[4ptg]] - hGSK-3 β + acylaminopyridine inhibitor<br />
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**[[3m1s]], [[3pup]] - hGSK-3 β + Ru complex<br />
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**[[4nm0]], [[4nm3]], [[4nu1]], [[1o9u]], [[4b7t]] - hGSK-3 β + Axin peptide<br />
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*GSK-3 ternary complex
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**[[2jld]] - hGSK-3 β + Ru complex + peptide<br />
 
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**[[3zdi]] - hGSK-3 β + Axin peptide + inhibitor<br />
 
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**[[4nm5]], [[4nm7]] - hGSK-3 β + Axin peptide + WNT receptor LRP6 peptide<br />
 
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}}
 
===References===
===References===
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Crystal Structure of Glycogen Synthase Kinase 3ß bound to Anticancer Ruthenium Complex (PDB code 3m1s)

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References

  1. ↑ Forde JE, Dale TC. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci. 2007 Aug;64(15):1930-44. PMID:17530463 doi:http://dx.doi.org/10.1007/s00018-007-7045-7
  2. ↑ Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets. 2006 Nov;7(11):1421-34. PMID:17100582
  3. ↑ Atilla-Gokcumen GE, Di Costanzo L, Meggers E. Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3beta. J Biol Inorg Chem. 2010 Sep 7. PMID:20821241 doi:10.1007/s00775-010-0699-x

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