Glycogen synthase kinase 3 - Revision history

Michal Harel at 08:59, 15 July 2019

Michal Harel — Mon, 15 Jul 2019 08:59:14 GMT

←Older revision		Revision as of 08:59, 15 July 2019
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	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.		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.

-	===3D structures of glycogen synthase kinase 3===	+	==3D structures of glycogen synthase kinase 3==
	[[Glycogen synthase kinase 3 3D structures]]		[[Glycogen synthase kinase 3 3D structures]]

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	</StructureSection>		</StructureSection>

-	===3D structures of glycogen synthase kinase 3===
-
-	Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
-	{{#tree:id=OrganizedByTopic\|openlevels=0\|
-
-	*GSK-3
-
-	**[[1i09]], [[1h8f]] – hGSK-3 β – human<br />
-	**[[4e7w]] – GSK-3 (mutant) – smut fungus<br />
-
-	*GSK-3 binary complex
-
-	**[[1gng]] - hGSK-3 β + Frattide peptide<br />
-	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94]], [[5f95]], [[5kpk]], [[5kpl]], [[5kpm]], [[6gjo]], [[6gn1]], [[6h0u]] - hGSK-3 β + inhibitor<br />
-	**[[5t31]] - hGSK-3 β (mutant) + inhibitor<br />
-	**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />
-	**[[1j1c]] - hGSK-3 β + ADP<br />
-	**[[1q3d]], [[1q3w]], [[1q41]] - hGSK-3 β + ATP-mimetic inhibitor<br />
-	**[[4ptc]], [[4pte]], [[4ptg]] - hGSK-3 β + acylaminopyridine inhibitor<br />
-	**[[3m1s]], [[3pup]] - hGSK-3 β + Ru complex<br />
-	**[[4nm0]], [[4nm3]], [[4nu1]], [[1o9u]], [[4b7t]] - hGSK-3 β + Axin peptide<br />
-	**[[6ae3]] - GSK-3 β + morin - mouse<br />
-
-	*GSK-3 ternary complex
-
-	**[[2jld]] - hGSK-3 β + Ru complex + peptide<br />
-	**[[3zdi]], [[6b8j]] - hGSK-3 β + Axin peptide + inhibitor<br />
-	**[[5oy4]] - hGSK-3 β + FRAT-1 peptide + inhibitor<br />
-	**[[4nm5]], [[4nm7]] - hGSK-3 β + Axin peptide + WNT receptor LRP6 peptide<br />
-	}}
	===References===		===References===
	<references/>		<references/>
	[[Category:Topic Page]]		[[Category:Topic Page]]

Michal Harel at 08:57, 15 July 2019

Michal Harel — Mon, 15 Jul 2019 08:57:35 GMT

←Older revision		Revision as of 08:57, 15 July 2019
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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> ==		== Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref> ==
	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.		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.
		+
		+	===3D structures of glycogen synthase kinase 3===
		+	[[Glycogen synthase kinase 3 3D structures]]
		+
		+
	</StructureSection>		</StructureSection>

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	**[[1gng]] - hGSK-3 β + Frattide peptide<br />		**[[1gng]] - hGSK-3 β + Frattide peptide<br />
-	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94]], [[5f95]], [[5kpk]], [[5kpl]], [[5kpm]] - hGSK-3 β + inhibitor<br />	+	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94]], [[5f95]], [[5kpk]], [[5kpl]], [[5kpm]], [[6gjo]], [[6gn1]], [[6h0u]] - hGSK-3 β + inhibitor<br />
	**[[5t31]] - hGSK-3 β (mutant) + inhibitor<br />		**[[5t31]] - hGSK-3 β (mutant) + inhibitor<br />
	**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />		**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />
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	**[[3m1s]], [[3pup]] - hGSK-3 β + Ru complex<br />		**[[3m1s]], [[3pup]] - hGSK-3 β + Ru complex<br />
	**[[4nm0]], [[4nm3]], [[4nu1]], [[1o9u]], [[4b7t]] - hGSK-3 β + Axin peptide<br />		**[[4nm0]], [[4nm3]], [[4nu1]], [[1o9u]], [[4b7t]] - hGSK-3 β + Axin peptide<br />
		+	**[[6ae3]] - GSK-3 β + morin - mouse<br />

	*GSK-3 ternary complex		*GSK-3 ternary complex

Michal Harel at 09:40, 4 June 2018

Michal Harel — Mon, 04 Jun 2018 09:40:04 GMT

←Older revision		Revision as of 09:40, 4 June 2018
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	**[[1gng]] - hGSK-3 β + Frattide peptide<br />		**[[1gng]] - hGSK-3 β + Frattide peptide<br />
-	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94]], [[5f95]] - hGSK-3 β + inhibitor<br />	+	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94]], [[5f95]], [[5kpk]], [[5kpl]], [[5kpm]] - hGSK-3 β + inhibitor<br />
		+	**[[5t31]] - hGSK-3 β (mutant) + inhibitor<br />
	**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />		**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />
	**[[1j1c]] - hGSK-3 β + ADP<br />		**[[1j1c]] - hGSK-3 β + ADP<br />
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	**[[2jld]] - hGSK-3 β + Ru complex + peptide<br />		**[[2jld]] - hGSK-3 β + Ru complex + peptide<br />
-	**[[3zdi]] - hGSK-3 β + Axin peptide + inhibitor<br />	+	**[[3zdi]], [[6b8j]] - hGSK-3 β + Axin peptide + inhibitor<br />
		+	**[[5oy4]] - hGSK-3 β + FRAT-1 peptide + inhibitor<br />
	**[[4nm5]], [[4nm7]] - hGSK-3 β + Axin peptide + WNT receptor LRP6 peptide<br />		**[[4nm5]], [[4nm7]] - hGSK-3 β + Axin peptide + WNT receptor LRP6 peptide<br />
	}}		}}

Michal Harel at 09:44, 1 June 2017

Michal Harel — Thu, 01 Jun 2017 09:44:59 GMT

←Older revision		Revision as of 09:44, 1 June 2017
Line 24:		Line 24:

	**[[1gng]] - hGSK-3 β + Frattide peptide<br />		**[[1gng]] - hGSK-3 β + Frattide peptide<br />
-	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94, [[5f95]] - hGSK-3 β + inhibitor<br />	+	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94]], [[5f95]] - hGSK-3 β + inhibitor<br />
	**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />		**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />
	**[[1j1c]] - hGSK-3 β + ADP<br />		**[[1j1c]] - hGSK-3 β + ADP<br />

Michal Harel at 09:44, 1 June 2017

Michal Harel — Thu, 01 Jun 2017 09:44:23 GMT

←Older revision		Revision as of 09:44, 1 June 2017
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	**[[1gng]] - hGSK-3 β + Frattide peptide<br />		**[[1gng]] - hGSK-3 β + Frattide peptide<br />
-	**[[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 />	+	**[[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]], [[5k5n]], [[5hlp]], [[5hln]], [[5f94, [[5f95]] - hGSK-3 β + inhibitor<br />
	**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />		**[[1pyx]], [[1j1b]] - hGSK-3 β + AMPPNP<br />
	**[[1j1c]] - hGSK-3 β + ADP<br />		**[[1j1c]] - hGSK-3 β + ADP<br />

Michal Harel at 09:04, 14 March 2016

Michal Harel — Mon, 14 Mar 2016 09:04:54 GMT

←Older revision		Revision as of 09:04, 14 March 2016
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	== Function ==		== Function ==
-	'''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. For more details see [[Student Project 9 for UMass Chemistry 423 Spring 2015]].	+	'''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]].

	== Relevance ==		== Relevance ==
-	GSK-3 inhibition is studied as a therapeutic target in diseases like Alzheimer, diabetes, bipolar disorder and some cancers.	+	GSK-3 inhibition is studied as a therapeutic target in diseases like Alzheimer, diabetes, bipolar disorder and some cancers<ref>PMID:17100582</ref>.

	== Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref> ==		== Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref> ==

Michal Harel at 08:54, 14 March 2016

Michal Harel — Mon, 14 Mar 2016 08:54:33 GMT

←Older revision		Revision as of 08:54, 14 March 2016
Line 1:		Line 1:
	<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]])'>		<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]])'>

-	'''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]].	+	== Function ==
		+	'''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. For more details see [[Student Project 9 for UMass Chemistry 423 Spring 2015]].

-	~~'''~~Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref>~~'''~~	+	== Relevance ==
		+	GSK-3 inhibition is studied as a therapeutic target in diseases like Alzheimer, diabetes, bipolar disorder and some cancers.
		+
		+	== Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref> ==
	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.		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.
	</StructureSection>		</StructureSection>

Michal Harel at 07:59, 14 March 2016

Michal Harel — Mon, 14 Mar 2016 07:59:03 GMT

←Older revision		Revision as of 07:59, 14 March 2016
Line 6:		Line 6:
	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.		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.
	</StructureSection>		</StructureSection>
-	__NOTOC__

	===3D structures of glycogen synthase kinase 3===		===3D structures of glycogen synthase kinase 3===

Michal Harel at 07:58, 14 March 2016

Michal Harel — Mon, 14 Mar 2016 07:58:36 GMT

←Older revision		Revision as of 07:58, 14 March 2016
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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]])'>	+	<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]])'>

	'''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]].		'''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]].

Michal Harel at 10:03, 22 February 2016

Michal Harel — Mon, 22 Feb 2016 10:03:41 GMT

←Older revision		Revision as of 10:03, 22 February 2016
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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]])'>		<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]])'>

-	'''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.	+	'''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]].

	'''Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref>'''		'''Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß <ref>DOI 10.1007/s00775-010-0699-x</ref>'''