1q4l: Difference between revisions
New page: left|200px<br /> <applet load="1q4l" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q4l, resolution 2.77Å" /> '''GSK-3 Beta complexe... |
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[[Image:1q4l.gif|left|200px]]<br /> | [[Image:1q4l.gif|left|200px]]<br /><applet load="1q4l" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1q4l" size=" | |||
caption="1q4l, resolution 2.77Å" /> | caption="1q4l, resolution 2.77Å" /> | ||
'''GSK-3 Beta complexed with Inhibitor I-5'''<br /> | '''GSK-3 Beta complexed with Inhibitor I-5'''<br /> | ||
==Overview== | ==Overview== | ||
GSK-3beta is a regulatory serine/threonine kinase with a plethora of | GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors. | ||
==About this Structure== | ==About this Structure== | ||
1Q4L 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 679 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:// | 1Q4L 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=679:'>679</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=1Q4L OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bertrand, J | [[Category: Bertrand, J A.]] | ||
[[Category: Cristiani, C.]] | [[Category: Cristiani, C.]] | ||
[[Category: Flocco, M.]] | [[Category: Flocco, M.]] | ||
[[Category: Kalisz, H | [[Category: Kalisz, H M.]] | ||
[[Category: Knapp, S.]] | [[Category: Knapp, S.]] | ||
[[Category: Thieffine, S.]] | [[Category: Thieffine, S.]] | ||
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[[Category: kinase]] | [[Category: kinase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:35:51 2008'' | ||
Revision as of 15:35, 21 February 2008
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GSK-3 Beta complexed with Inhibitor I-5
OverviewOverview
GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors.
About this StructureAbout this Structure
1Q4L 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.
ReferenceReference
Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors., Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M, J Mol Biol. 2003 Oct 17;333(2):393-407. PMID:14529625
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