2clq: Difference between revisions

Revision as of 17:49, 21 February 2008

STRUCTURE OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5

OverviewOverview

Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Analytical ultracentrifugation (AUC) and crystallographic analysis showed that ASK1 forms a tight dimer (K(d) approximately 0.2 microM) interacting in a head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ from known ASK1 phosphorylation sites but correspond well to autophosphorylation sites identified by mass spectrometry. Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed mutants showed catalytic activities similar to wild-type ASK1, suggesting a regulatory mechanism independent of ASK1 kinase activity. The determined high-resolution structure of ASK1 and identified ATP mimetic inhibitors will provide a first starting point for the further development of selective inhibitors.

About this StructureAbout this Structure

2CLQ is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25 Known structural/functional Sites: and . Full crystallographic information is available from OCA.

ReferenceReference

Structural and functional characterization of the human protein kinase ASK1., Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Muller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S, Structure. 2007 Oct;15(10):1215-26. PMID:17937911

Page seeded by OCA on Thu Feb 21 16:49:57 2008

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OCA

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 ==Overview==
-Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in, stress and immune response and has been linked to the development of, several diseases. Here, we present the structure of the human ASK1, catalytic domain in complex with staurosporine. Analytical, ultracentrifugation (AUC) and crystallographic analysis showed that ASK1, forms a tight dimer (K(d) approximately 0.2 muM) interacting in a, head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ, from known ASK1 phosphorylation sites but correspond well to, autophosphorylation sites identified by mass spectrometry. Reporter gene, assays showed that all three identified in vitro autophosphorylation sites, (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed, mutants showed catalytic activities similar to wild-type ASK1, suggesting, a regulatory mechanism independent of ASK1 kinase activity. The determined, high-resolution structure of ASK1 and identified ATP mimetic inhibitors, will provide a first starting point for the further development of, selective inhibitors.
+Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Analytical ultracentrifugation (AUC) and crystallographic analysis showed that ASK1 forms a tight dimer (K(d) approximately 0.2 microM) interacting in a head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ from known ASK1 phosphorylation sites but correspond well to autophosphorylation sites identified by mass spectrometry. Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed mutants showed catalytic activities similar to wild-type ASK1, suggesting a regulatory mechanism independent of ASK1 kinase activity. The determined high-resolution structure of ASK1 and identified ATP mimetic inhibitors will provide a first starting point for the further development of selective inhibitors.
 ==About this Structure==
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 ==Reference==
-Structural and Functional Characterization of the Human Protein Kinase ASK1., Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Muller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S, Structure. 2007 Oct;15(10):1215-26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17937911 17937911]
+Structural and functional characterization of the human protein kinase ASK1., Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Muller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S, Structure. 2007 Oct;15(10):1215-26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17937911 17937911]
 [[Category: Homo sapiens]]
 [[Category: Mitogen-activated protein kinase kinase kinase]]
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 [[Category: Arrowsmith, C.]]
 [[Category: Bunkoczi, G.]]
-[[Category: Delft, F.Von.]]
+[[Category: Delft, F Von.]]
 [[Category: Edwards, A.]]
 [[Category: Fedorov, O.]]
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 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:36:42 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:49:57 2008''