2clq
STRUCTURE OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
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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 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 StructureAbout 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.
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
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