Ligand discrimination between active and inactive activation loop conformations of Aurora-A kinase is unmodified by phosphorylation

• DOI: 10.1039/c8sc03669a
• Publication Date: 2019-03-04T14:05:14Z
• Authors: James A. H. Gilburt; Paul Girvan; Julian Blagg; Liming Ying; Charlotte A. Dodson
• Keywords: /dk/atira/pure/subjectarea/asjc/1600/1606; 570; Chemistry; 0303 health sciences; 03 medical and health sciences; /dk/atira/pure/subjectarea/asjc/1600/1605; Organic Chemistry; Biophysics; Physical and Theoretical Chemistry; 540; /dk/atira/pure/subjectarea/asjc/1300/1304

Structure-based drug design is commonly used to guide the development of potent and specific enzyme inhibitors. Many enzymes - such as protein kinases adopt multiple conformations, conformational interconversion expected impact on small molecule We measured dynamic equilibrium between DFG-in-like active DFG-out-like inactive conformations activation loop unphosphorylated Aurora-A alone, in presence activator TPX2, kinase The had a shorter residence time conformation shift position towards compared with phosphorylated for all conditions measured. Ligand binding was associated change which each ligand independent phosphorylation state. As consequence this, ability discriminate also phosphorylation. Importantly, we discovered that can lead plateau overall K d, despite increasing affinity chosen target conformation, modelled discrimination necessary conformation-promoting ligand.