Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states.

ABSTRACT: Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states. Profiling a panel of clinically relevant Aurora kinase inhibitors against the mitotic kinase Aurora A revealed a wide range of conformational preferences, with all inhibitors promoting either the active DFG-in state or the inactive DFG-out

SUBMITTER: Lake EW 

PROVIDER: S-EPMC6304972 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature