2clq
From Proteopedia
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caption="2clq, resolution 2.30Å" /> | caption="2clq, resolution 2.30Å" /> | ||
'''STRUCTURE OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5'''<br /> | '''STRUCTURE OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5'''<br /> | ||
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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. | ||
==About this Structure== | ==About this Structure== | ||
| - | 2CLQ 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 STU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] Structure known Active | + | 2CLQ 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 STU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] Structure known Active Sites: AC1 and AC2. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CLQ OCA]. |
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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] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mitogen-activated protein kinase kinase kinase]] | [[Category: Mitogen-activated protein kinase kinase kinase]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:16:56 2007'' |
Revision as of 19:10, 12 November 2007
|
STRUCTURE OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
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.
About this Structure
2CLQ is a Single protein structure of sequence from Homo sapiens with STU as ligand. Active as Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25 Structure known Active Sites: AC1 and AC2. Full crystallographic information is available from OCA.
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:17937911
Page seeded by OCA on Mon Nov 12 21:16:56 2007
Categories: Homo sapiens | Mitogen-activated protein kinase kinase kinase | Single protein | Arrowsmith, C. | Bunkoczi, G. | Delft, F.Von. | Edwards, A. | Fedorov, O. | Gileadi, O. | Knapp, S. | Pike, A. | Salah, E. | Sundstrom, M. | Weigelt, J. | STU | Apoptosis | Atp-binding | Kinase | Magnesium | Map kinase | Metal-binding | Nucleotide-binding | Phosphorylation | Protein kinase | Serine/threonine-protein kinase | Transferase
