Conformational selection vs. induced fit: insights into the binding mechanisms of p38α MAP Kinase inhibitors
Patrick Roser1, Jörn Weisner2, Juliane Stehle1
1Department of Chemistry and Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Universitätsstraße 10, 78457 Konstanz, Germany. malte.drescher@uni-konstanz.de.
Abstract:
The conformational dynamics of a kinase's activation loop have been challenging to assess due to the activation loop's intrinsic flexibility. To directly probe the conformational equilibrium of the activation loop of mitogen-activated protein kinase p38α, we present an approach based on site-directed spin labeling, electron paramagnetic resonance (EPR) distance restraints, and multilateration. We demonstrate that the activation loop of apo p38α resides in a highly flexible equilibrium state and we reveal that binding of small molecules significantly alters this equilibrium and the populated sub-states.
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