6zpr

Solution structure of MLKL executioner domain in complex with a covalent inhibitor

Structural highlights

6zpr is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	QOK
Related:	6zle
Gene:	MLKL (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MLKL_HUMAN] Required for the execution of programmed necrosis.^[1]

Publication Abstract from PubMed

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 alpha6 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.

Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.,Rubbelke M, Fiegen D, Bauer M, Binder F, Hamilton J, King J, Thamm S, Nar H, Zeeb M Proc Natl Acad Sci U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012 Jan 20;148(1-2):228-43. doi: 10.1016/j.cell.2011.11.030. PMID:22265414 doi:https://dx.doi.org/10.1016/j.cell.2011.11.030
↑ 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 U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170 doi:https://dx.doi.org/10.1073/pnas.2017406117

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012 Jan 20;148(1-2):228-43. doi: 10.1016/j.cell.2011.11.030. PMID:22265414 doi:https://dx.doi.org/10.1016/j.cell.2011.11.030

[2] 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 U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170 doi:https://dx.doi.org/10.1073/pnas.2017406117

[1]

[2]

6zpr

Solution structure of MLKL executioner domain in complex with a covalent inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools