5KO1

Pseudokinase Domain of MLKL bound to Compound 4.

5KO1 の概要

• エントリーDOI: 10.2210/pdb5ko1/pdb
• 関連するPDBエントリー: 5KNJ
• 分子名称: Mixed lineage kinase domain-like protein, [(1~{R})-2-[(4-fluorophenyl)amino]-2-oxidanylidene-1-phenyl-ethyl] 3-azanylpyrazine-2-carboxylate (3 entities in total)
• 機能のキーワード: pseudokinase domain mlkl type1 inhibitor, membrane proteins-inhibitor complex, membrane proteins/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q8NB16
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32599.51

構造登録者

Marcotte, D.J. (登録日: 2016-06-29, 公開日: 2016-11-16, 最終更新日: 2023-09-27)

主引用文献

Ma, B.,Marcotte, D.,Paramasivam, M.,Michelsen, K.,Wang, T.,Bertolotti-Ciarlet, A.,Jones, J.H.,Moree, B.,Butko, M.,Salafsky, J.,Sun, X.,McKee, T.,Silvian, L.F.
ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis.
Plos One, 11:e0165983-e0165983, 2016

PubMed Abstract: MLKL is a pore forming pseudokinase involved in the final stage of necroptosis, a form of programmed cell death. Its phosphorylation by RIPK3 is necessary for triggering necroptosis but not for triggering apoptosis, which makes it a unique target for pharmacological inhibition to block necroptotic cell death. This mechanism has been described as playing a role in disease progression in neurodegenerative and inflammatory diseases. A type II kinase inhibitor (cpd 1) has been described that reportedly binds to the MLKL pseudokinase domain and prevents necroptosis. Here we describe five compounds that bind to the MLKL ATP-binding site, however the four MLKL-selective compounds have no activity in rescuing cells from necroptosis. We use kinase selectivity panels, crystallography and a new conformationally sensitive method of measuring protein conformational changes (SHG) to confirm that the one previously reported compound that can rescue cells (cpd 1) is a non-selective type II inhibitor that also inhibits the upstream kinase RIPK1. Although this compound can shift the GFE motif of the activation loop to an "out" position, the accessibility of the key residue Ser358 in the MLKL activation loop is not affected by compound binding to the MLKL active site. Our studies indicate that an ATP-pocket inhibitor of the MLKL pseudokinase domain does not have any impact on the necroptosis pathway, which is contrary to a previously reported study.

PubMed: 27832137
DOI: 10.1371/journal.pone.0165983

実験手法

X-RAY DIFFRACTION (2.16 Å)