Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases

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.</p

Asteroseismology of the Hyades red giant and planet host epsilon Tauri

Asteroseismic analysis of solar-like stars allows us to determine physical parameters such as stellar mass, with a higher precision compared to most other methods. Even in a well-studied cluster such as the Hyades, the masses of the red giant stars are not well known, and previous mass estimates are based on model calculations (isochrones). The four known red giants in the Hyades are assumed to be clump (core-helium-burning) stars based on their positions in colour-magnitude diagrams, however asteroseismology offers an opportunity to test this assumption. Using asteroseismic techniques combined with other methods, we aim to derive physical parameters and the evolutionary stage for the planet hosting star epsilon Tau, which is one of the four red giants located in the Hyades. We analysed time-series data from both ground and space to perform the asteroseismic analysis. By combining high signal-to-noise (S/N) radial-velocity data from the ground-based SONG network with continuous space-based data from the revised Kepler mission K2, we derive and characterize 27 individual oscillation modes for epsilon Tau, along with global oscillation parameters such as the large frequency separation and the ratio between the amplitude of the oscillations measured in radial velocity and intensity as a function of frequency. The latter has been measured previously for only two stars, the Sun and Procyon. Combining the seismic analysis with interferometric and spectroscopic measurements, we derive physical parameters for epsilon Tau, and discuss its evolutionary status.Comment: 13 pages, 13 figures, 4 tables, accepted for publication in Astronomy & Astrophysic