Abstract:
:As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix α6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action.
journal_name
Proc Natl Acad Sci U S Aauthors
Rübbelke M,Fiegen D,Bauer M,Binder F,Hamilton J,King J,Thamm S,Nar H,Zeeb Mdoi
10.1073/pnas.2017406117subject
Has Abstractpub_date
2020-12-29 00:00:00pages
33272-33281issue
52eissn
0027-8424issn
1091-6490pii
2017406117journal_volume
117pub_type
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