Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL

James M Murphy, Isabelle Lucet, Joanne M Hildebrand, Maria C Tanzer, Samuel N Young, Pooja Sharma, Guillaume Lessene, Warren Alexander, Jeffrey Babon, John Silke, Peter Edward Czabotar

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55 Citations (Scopus)


The pseudokinase MLKL (mixed lineage kinase domain-like) was identified recently as an essential checkpoint in the programmed necrosis or necroptosis cell death pathway. In the present study, we report the crystal structure of the human MLKL pseudokinase domain at 1.7 A (1 A=0.1 nm) resolution and probe its nucleotide-binding mechanism by performing structure-based mutagenesis. By comparing the structures and nucleotide-binding determinants of human and mouse MLKL orthologues, the present study provides insights into the evolution of nucleotide-binding mechanisms among pseudokinases and their mechanistic divergence from conventional catalytically active protein kinases.
Original languageEnglish
Pages (from-to)369 - 377
Number of pages9
JournalBiochemical Journal
Issue number3
Publication statusPublished - 2014

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