7JW7

Structure of monobody 27 human MLKL pseudokinase domain complex

7JW7 の概要

• エントリーDOI: 10.2210/pdb7jw7/pdb
• 分子名称: Mixed lineage kinase domain-like protein, Monobody 27 (3 entities in total)
• 機能のキーワード: pseudokinase, monobody, complex, necroptosis, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43403.42

構造登録者

Meng, Y.,Garnish, S.E.,Koide, A.,Koide, S.,Czabotar, P.E.,Murphy, J.M. (登録日: 2020-08-25, 公開日: 2021-03-10, 最終更新日: 2023-10-18)

主引用文献

Garnish, S.E.,Meng, Y.,Koide, A.,Sandow, J.J.,Denbaum, E.,Jacobsen, A.V.,Yeung, W.,Samson, A.L.,Horne, C.R.,Fitzgibbon, C.,Young, S.N.,Smith, P.P.C.,Webb, A.I.,Petrie, E.J.,Hildebrand, J.M.,Kannan, N.,Czabotar, P.E.,Koide, S.,Murphy, J.M.
Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis.
Nat Commun, 12:2211-2211, 2021

PubMed Abstract: Phosphorylation of the MLKL pseudokinase by the RIPK3 kinase leads to MLKL oligomerization, translocation to, and permeabilization of, the plasma membrane to induce necroptotic cell death. The precise choreography of MLKL activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind the pseudokinase domain of MLKL within human cells and their crystal structures in complex with the human MLKL pseudokinase domain. While Monobody-32 constitutively binds the MLKL hinge region, Monobody-27 binds MLKL via an epitope that overlaps the RIPK3 binding site and is only exposed after phosphorylated MLKL disengages from RIPK3 following necroptotic stimulation. The crystal structures identified two distinct conformations of the MLKL pseudokinase domain, supporting the idea that a conformational transition accompanies MLKL disengagement from RIPK3. These studies provide further evidence that MLKL undergoes a large conformational change upon activation, and identify MLKL disengagement from RIPK3 as a key regulatory step in the necroptosis pathway.

PubMed: 33850121
DOI: 10.1038/s41467-021-22400-z

実験手法

X-RAY DIFFRACTION (2.63 Å)