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

Chem Commun (Camb). 2020 Aug 4;56(62):8818-8821. doi: 10.1039/d0cc02539a.

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.

MeSH terms

  • 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

Substances

  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 14