Abstract
Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 Å resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.
Highlights
Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and multiple sclerosis
We find that DMF inhibits ribosomal S6 kinases (RSKs)/Mitogen and Stress-activated Kinases (MSKs) 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 Ribosomal S6 Kinase 2 (RSK2) C-terminal kinase domain (CTKD), but at moderate efficacy with an IC50, app. of 225 μM, when incubated with RSK2CTKD prior to ERK2 activation, whereas monomethyl fumarate (MMF) displayed no inhibition of RSK2CTKD (Fig. 1c)
Summary
Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and multiple sclerosis. A proposed MOA for DMF treatment of MS and psoriasis builds on GSH depletion increasing hemoxygenase-1 expression, impairing STAT1 (signal transducer and activator of transcription 1) phosphorylation, and hereby inhibiting Th1 and Th17 (T helper cell 1 and 17) differentiation[6,7]. DMF inhibition of Th1 and Th17 differentiation has been demonstrated through suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), p38 MAPK (mitogen-activated protein kinase) and ERK1/2 (extracelluar signal-regulated kinase 1 and 2) signalling pathways[8,10] Along this line, DMF was identified as a NF-κB inhibitor[11], and targeting the C-terminal kinase domain (CTKD) of the ribosomal S6 kinases (RSKs)[12] and mitogen- and stress-activated kinases (MSKs)[13]. 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
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