Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 38, Pages 11409-11414Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201704654
Keywords
activation loop; Aurora A; drug design; kinases; single-molecule studies
Categories
Funding
- BBSRC [BB/M021149/1, JF20607/2, BB/G00954X/1]
- Cancer Research UK [C309/A11566]
- Biotechnology and Biological Sciences Research Council [JF20607/2, BB/M021149/1, BB/G00594X/1] Funding Source: researchfish
- Cancer Research UK [11566] Funding Source: researchfish
- BBSRC [BB/M021149/1, BB/G00594X/1] Funding Source: UKRI
Ask authors/readers for more resources
The conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small-molecule inhibitors. By using single-molecule fluorescence spectroscopy, we have determined that phosphorylated Aurora A kinase is in dynamic equilibrium between a DFG-in-like active T-loop conformation and a DFG-out-like inactive conformation, and have measured the rate constants of interconversion. Addition of the Aurora A activating protein TPX2 shifts the equilibrium towards an active T-loop conformation whereas addition of the inhibitors MLN8054 and CD532 favors an inactive T-loop. We show that Aurora A binds TPX2 and MLN8054 simultaneously and provide a new model for kinase conformational behavior. Our approach will enable conformation-specific effects to be integrated into inhibitor discovery across the kinome, and we outline some immediate consequences for structure-based drug discovery.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available