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Department Seminar: What makes a kinase promiscuous for inhibitors?
April 18, 2018 @ 1:30 pm - 2:30 pm
What makes a kinase promiscuous for inhibitors?
Post-Doctoral Fellow, Memorial Sloan Kettering Cancer Center.
Wed, April 18, 2018
1:30 PM – 2:30 PM
Natural Sciences II, Room 2201
ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through hierarchical clustering analysis of kinome profiling data of a large inhibitor set (containing 406 kinases and 645 ligands) we found a set of unusually promiscuous kinases. From these promiscuous kinases, we focused on DDR1, an unusual receptor tyrosine kinase (RTK) characterized by slow activation kinetics, low kinase activity, and not a clinical target. Co-crystallization of DDR1 with VX-680 and dasatinib revealed a unique salt bridge between the activation loop and C-lobe of DDR1, stabilizing the inactive conformation. Using computational simulations and mutational analysis, we determined that DDR1 has a relatively stable DFG-Asp-Out conformation. We propose that the promiscuous behavior of DDR1 and other promiscuous tyrosine kinases is related to its stable inactive conformation, which forms a binding pocket capable of binding a chemically diverse range of inhibitors.
About Sonya Hanson
Sonya Hanson is a Postdoctoral Fellow at Memorial Sloan Kettering Cancer Center. She received her PhD (DPhil) in Biochemistry in 2014 from Oxford and is now working in the lab of John Chodera combining experimental measurements and computational models to understand how to make better cancer drugs, specifically kinase inhibitors.