Conformational selection vs. induced fit: insights into the binding mechanisms of p38α MAP Kinase inhibitors

• Published in: Chemical communications (Cambridge, England) Vol. 56; no. 62; pp. 8818 - 8821
• Main Authors: Roser, Patrick, Weisner, Jörn, Stehle, Juliane, Rauh, Daniel, Drescher, Malte
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 04.08.2020
• Subjects: Activation; Binding; Electron paramagnetic resonance; Electron spin; Kinases; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 14 - chemistry; Mitogen-Activated Protein Kinase 14 - metabolism; Models, Molecular; Protein Binding; Protein Conformation; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Substrate Specificity
• ISSN: 1359-7345; 1364-548X
• DOI: 10.1039/d0cc02539a

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.