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- Title
Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1.
- Authors
Hindie, Valerie; Stroba, Adriana; Zhang, Hua; Lopez-Garcia, Laura A.; Idrissova, Leila; Zeuzem, Stefan; Hirschberg, Daniel; Schaeffer, Francis; Jørgensen, Thomas J. D.; Engel, Matthias; Alzari, Pedro M.; Biondi, Ricardo M.
- Abstract
Protein phosphorylation transduces a large set of intracellular signals. One mechanism by which phosphorylation mediates signal transduction is by prompting conformational changes in the target protein or interacting proteins. Previous work described an allosteric site mediating phosphorylation-dependent activation of AGC kinases. The AGC kinase PDK1 is activated by the docking of a phosphorylated motif from substrates. Here we present the crystallography of PDK1 bound to a rationally developed low-molecular-weight activator and describe the conformational changes induced by small compounds in the crystal and in solution using a fluorescence-based assay and deuterium exchange experiments. Our results indicate that the binding of the compound produces local changes at the target site, the PIF binding pocket, and also allosteric changes at the ATP binding site and the activation loop. Altogether, we present molecular details of the allosteric changes induced by small compounds that trigger the activation of PDK1 through mimicry of phosphorylation-dependent conformational changes.
- Subjects
INTRACELLULAR pathogens; ALLOSTERIC regulation; PLASMINOGEN activators; PHOSPHORYLATION; PROTEIN kinases; MOLECULAR weights
- Publication
Nature Chemical Biology, 2009, Vol 5, Issue 10, p758
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.208