Open AccessLocking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis
Author(s) -
Martin Rübbelke,
Dennis Fiegen,
Margit Bauer,
Florian Binder,
James A. Hamilton,
Jim King,
Sven Thamm,
Herbert Nar,
Markus Zeeb
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2017406117
Subject(s) - necroptosis , microbiology and biotechnology , programmed cell death , effector , ripk1 , proinflammatory cytokine , kinase , biology , cysteine , chemistry , apoptosis , biochemistry , inflammation , enzyme , immunology
Significance Necroptosis is an emergency controlled cell-death mechanism, which only may be activated in case of impaired apoptosis. Necroptosis leads to unchecked release of proinflammatory cytoplasmatic content of the cells and is thereby implicated in disease. Two covalent inhibitor classes targeting the same cysteine of the necroptosis effector protein mixed-lineage kinase domain-like protein (MLKL) are reported. Here, we unravel the mode of action of the xanthine class of inhibitors that work by stabilizing the inactive state of MLKL by an essential π–π stacking interaction. The widely used covalent tool compound Necrosulfonamide (NSA) employs a distinct mode of action.