News Finding: Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory aL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition.
Paper Finding: We found that DMF leads to full inhibition of RSK2 CTKD , but at moderate efficacy with an IC 50, app.
News Context: DMFreacts covalently as a Michael acceptor to a conserved cysteine residue in the aF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory aL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. Very importantly, the team found that dimethyl fumarate reacts covalently with at a specific site of the RSK2 protein, which is found in all the RSK and MSK protein kinases, and that this reaction prevents these protein kinases from becoming activated.
Paper Context: We find that DMF inhibits RSK/MSK kinases primarily by covalent binding to a conserved cysteine residue placed at an allosteric site, and that this interaction is likely to represent an important component of the mechanism of action of DMF as a clinical drug. We found that DMF leads to full inhibition of RSK2 CTKD , but at moderate efficacy with an IC 50, app. of 225 μM, when incubated with RSK2 CTKD prior to ERK2 activation, whereas MMF displayed no inhibition of RSK2 CTKD (Fig.