PDBsum entry 4btf

Transferase

PDB id: 4btf

Contents

Protein chain

413 a.a.

Ligands

FMT

EDO ×2

Waters ×41

PDB id:

4btf

Name:

Transferase

Title:

Structure of mlkl

Structure:

Mixed lineage kinase domain-like protein. Chain: a. Synonym: mlkl. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

2.60Å R-factor: 0.209 R-free: 0.256

Authors:

P.E.Czabotar,J.M.Murphy

Key ref:

J.M.Murphy et al. (2013). The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity, 39, 443-453. PubMed id: 24012422 DOI: 10.1016/j.immuni.2013.06.018

Date:

16-Jun-13 Release date: 18-Sep-13

Protein chain

Q9D2Y4  (MLKL_MOUSE) -  Mixed lineage kinase domain-like protein from Mus musculus

Seq: 472 a.a.

Struc: 413 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.immuni.2013.06.018

Immunity 39:443-453 (2013)

PubMed id: 24012422

The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism.

J.M.Murphy, P.E.Czabotar, J.M.Hildebrand, I.S.Lucet, J.G.Zhang, S.Alvarez-Diaz, R.Lewis, N.Lalaoui, D.Metcalf, A.I.Webb, S.N.Young, L.N.Varghese, G.M.Tannahill, E.C.Hatchell, I.J.Majewski, T.Okamoto, R.C.Dobson, D.J.Hilton, J.J.Babon, N.A.Nicola, A.Strasser, J.Silke, W.S.Alexander.

ABSTRACT

Mixed lineage kinase domain-like (MLKL) is a component of the "necrosome," the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice were viable and displayed no hematopoietic anomalies or other obvious pathology, cells derived from these animals were resistant to TNF-induced necroptosis unless MLKL expression was restored. Structurally, MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation. Structure-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification of MLKL is essential for propagation of the necroptosis pathway downstream of RIPK3.