Lipid Pocket Binders Impose Allosteric Changes of Protein Dynamics Around the Active Site of the Protein Kinase p38α

Protein kinases represent major pharmaceutical targets, but the development of selective modulators remains challenging. In search of allosteric sites in the serine/threonine kinase p38α, a "lipid pocket" in the C-lobe has been found to bear prospects for the binding of small molecules. A pharmacological potential of those low-affinity binders found initially has not become obvious, however, raising the overarching question whether any sort of communication between this pocket and the enzyme's functional sites exists. Here, we use NMR spectroscopy to reveal an effective connectivity of these sites in spite of their spatial distance. The data reveal a clear interdependency of protein dynamics between the different structural elements through dynamic allostery, together suggesting a pharmacological avenue for the development of suitable lipid pocket binders to allosterically alter enzymatic functionality in a disease context.