mixed lineage kinase domain like pseudokinase | TKL-unique family | IUPHAR/BPS Guide to PHARMACOLOGY

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mixed lineage kinase domain like pseudokinase

target has curated data in GtoImmuPdb

Target id: 2106

Nomenclature: mixed lineage kinase domain like pseudokinase

Abbreviated Name: MLKL

Family: TKL-unique family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 471 16q22.3 MLKL mixed lineage kinase domain like pseudokinase
Mouse - 464 8 D3 Mlkl mixed lineage kinase domain-like
Rat - 464 19q12 Mlkl mixed lineage kinase domain like pseudokinase
Previous and Unofficial Names
mixed lineage kinase domain-like | mixed lineage kinase domain like
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Pseudokinase domain of MLKL bound to compound 1.
PDB Id:  5KNJ
Ligand:  MLKL compound 1
Resolution:  2.88Å
Species:  Human
References:  3

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MLKL compound 1 Hs Inhibition 6.3 – 7.0 pIC50 2
pIC50 6.3 – 7.0 (IC50 5x10-7 – 1x10-7 M) [2]
Description: Inhibition of TSQ-induced necroptosis in cellular assays.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MLKL compound 1 Hs Binding 5.0 pKd 2
pKd 5.0 (Kd 9.3x10-6 M) [2]
Description: Surface plasmon resonance (SPR) assay.
Immunopharmacology Comments
We have included MLKL in the Guide to IMMUNOPHARMACOLOGY because of its essential role in the necroptosis pathway- necroptosis being a regulated type of necrosis, or inflammatory cell death involving RIPK3 [4] and MLKL [5]. Necroptosis can be induced by a variety of mediators, including death receptors [1], interferons, Toll-like receptors and intracellular RNA and DNA sensors (and possibly others).
General Comments
MLKL is a pore forming pseudokinase involved in triggering necroptosis, a function regulated by phosphorylation by upstream RIPK3. It is not required for apoptosis. This protein has no detectable kinase activity but does have a nucleotide binding domain. Nucleotide binding promotes a conformational change that enables exposure of the N-terminal four-helix bundle domain, that facilitates membrane localization and necroptotic cell death [2].

References

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1. Bittner S, Knoll G, Ehrenschwender M. (2017) Death receptor 3 mediates necroptotic cell death. Cell. Mol. Life Sci., 74 (3): 543-554. [PMID:27592300]

2. Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier JM, Dobson RC, Webb AI et al.. (2014) Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc. Natl. Acad. Sci. U.S.A., 111 (42): 15072-7. [PMID:25288762]

3. Ma B, Marcotte D, Paramasivam M, Michelsen K, Wang T, Bertolotti-Ciarlet A, Jones JH, Moree B, Butko M, Salafsky J et al.. (2016) ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis. PLoS ONE, 11 (11): e0165983. [PMID:27832137]

4. Orozco S, Oberst A. (2017) RIPK3 in cell death and inflammation: the good, the bad, and the ugly. Immunol. Rev., 277 (1): 102-112. [PMID:28462521]

5. Pasparakis M, Vandenabeele P. (2015) Necroptosis and its role in inflammation. Nature, 517 (7534): 311-20. [PMID:25592536]

How to cite this page

TKL-unique family: mixed lineage kinase domain like pseudokinase. Last modified on 29/08/2017. Accessed on 12/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2106.