6ZVO

Crystal structure of unliganded MLKL executioner domain

Summary for 6ZVO

• Entry DOI: 10.2210/pdb6zvo/pdb
• Related: 6zle 6zpr
• Descriptor: Mixed lineage kinase domain-like protein, CHLORIDE ION, BROMIDE ION, ... (4 entities in total)
• Functional Keywords: necroptosis, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 53113.24

Authors

Fiegen, D.,Bauer, M.,Nar, H. (deposition date: 2020-07-27, release date: 2020-12-23, Last modification date: 2024-01-31)

Primary citation

Rubbelke, M.,Fiegen, D.,Bauer, M.,Binder, F.,Hamilton, J.,King, J.,Thamm, S.,Nar, H.,Zeeb, M.
Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.
Proc.Natl.Acad.Sci.USA, 117:33272-33281, 2020

PubMed 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.

PubMed: 33318170
DOI: 10.1073/pnas.2017406117

Experimental method

X-RAY DIFFRACTION (1.371 Å)