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1q5k
From Proteopedia
(New page: 200px<br /> <applet load="1q5k" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q5k, resolution 1.94Å" /> '''crystal structure o...) |
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| - | [[Image:1q5k.gif|left|200px]]<br /> | + | [[Image:1q5k.gif|left|200px]]<br /><applet load="1q5k" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1q5k" size=" | + | |
caption="1q5k, resolution 1.94Å" /> | caption="1q5k, resolution 1.94Å" /> | ||
'''crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor'''<br /> | '''crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has | + | Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5. |
==About this Structure== | ==About this Structure== | ||
| - | 1Q5K is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with TMU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http:// | + | 1Q5K is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=TMU:'>TMU</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q5K OCA]. |
==Reference== | ==Reference== | ||
| Line 24: | Line 23: | ||
[[Category: Hernandez, F.]] | [[Category: Hernandez, F.]] | ||
[[Category: Jerning, E.]] | [[Category: Jerning, E.]] | ||
| - | [[Category: Lucas, J | + | [[Category: Lucas, J J.]] |
| - | [[Category: Markgren, P | + | [[Category: Markgren, P O.]] |
[[Category: Nilsson, Y.]] | [[Category: Nilsson, Y.]] | ||
[[Category: Nylof, M.]] | [[Category: Nylof, M.]] | ||
[[Category: Ormo, M.]] | [[Category: Ormo, M.]] | ||
| - | [[Category: Radesater, A | + | [[Category: Radesater, A C.]] |
[[Category: Xue, Y.]] | [[Category: Xue, Y.]] | ||
[[Category: TMU]] | [[Category: TMU]] | ||
[[Category: kinase-inhibitor complex]] | [[Category: kinase-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:36:05 2008'' |
Revision as of 12:36, 21 February 2008
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crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor
Overview
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
About this Structure
1Q5K is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418., Bhat R, Xue Y, Berg S, Hellberg S, Ormo M, Nilsson Y, Radesater AC, Jerning E, Markgren PO, Borgegard T, Nylof M, Gimenez-Cassina A, Hernandez F, Lucas JJ, Diaz-Nido J, Avila J, J Biol Chem. 2003 Nov 14;278(46):45937-45. Epub 2003 Aug 19. PMID:12928438
Page seeded by OCA on Thu Feb 21 14:36:05 2008
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Single protein | Avila, J. | Berg, S. | Bhat, R. | Borgegard, T. | Diaz-Mido, J. | Gimenez-Cassina, A. | Hellberg, S. | Hernandez, F. | Jerning, E. | Lucas, J J. | Markgren, P O. | Nilsson, Y. | Nylof, M. | Ormo, M. | Radesater, A C. | Xue, Y. | TMU | Kinase-inhibitor complex
