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mixed lineage kinase domain like pseudokinase

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2106

Nomenclature: mixed lineage kinase domain like pseudokinase

Abbreviated Name: MLKL

Family: TKL-unique family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 471 16q23.1 MLKL mixed lineage kinase domain like pseudokinase
Mouse - 472 8 E1 Mlkl mixed lineage kinase domain-like
Rat - 464 19q12 Mlkl mixed lineage kinase domain like pseudokinase
Previous and Unofficial Names Click here for help
mixed lineage kinase domain-like | mixed lineage kinase domain like
Database Links Click here for help
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
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UniProtKB
Wikipedia
Selected 3D Structures Click here for help
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:  5

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 56 [PMID: 36136378] Small molecule or natural product Hs Inhibition 7.1 pEC50 2
pEC50 7.1 (EC50 8.2x10-8 M) [2]
Description: Inhibition of induced necroptosis in HT-29 cells
MLKL compound 1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 – 7.0 pIC50 3
pIC50 6.3 – 7.0 (IC50 5x10-7 – 1x10-7 M) [3]
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 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Binding 5.0 pKd 3
pKd 5.0 (Kd 9.3x10-6 M) [3]
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 that is associated with tissue damage in a range of proinflammatory diseases, including chronic obstructive pulmonary disease, atherosclerosis, acute colitis, psoriasis and atherosclerosis [4,8-9]. The receptor interacting protein kinases RIPK1 and RIPK3 [6], and pseudokinase MLKL [7] are the core regulators of necroptosis. As such, these 3 proteins are being pursued as molecular targets for the development of drugs that can be used to treat necroptosis-related diseases.

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 [3].

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. Cui B, Yan B, Wang K, Li L, Chen S, Zhang Z. (2022) Discovery of a New Class of Uracil Derivatives as Potential Mixed Lineage Kinase Domain-like Protein (MLKL) Inhibitors. J Med Chem, 65 (19): 12747-12780. [PMID:36136378]

3. 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 USA, 111 (42): 15072-7. [PMID:25288762]

4. Kang K, Park C, Chan FK. (2022) Necroptosis at a glance. J Cell Sci, 135 (17). DOI: 10.1242/jcs.260091 [PMID:36098620]

5. 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]

6. 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]

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

8. Puylaert P, Zurek M, Rayner KJ, De Meyer GRY, Martinet W. (2022) Regulated Necrosis in Atherosclerosis. Arterioscler Thromb Vasc Biol, 42 (11): 1283-1306. [PMID:36134566]

9. Zhou W, Yuan J. (2014) Necroptosis in health and diseases. Semin Cell Dev Biol, 35: 14-23. [PMID:25087983]

How to cite this page

TKL-unique family: mixed lineage kinase domain like pseudokinase. Last modified on 26/09/2022. Accessed on 12/07/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2106.