6o5z

Crystal Structure of the human MLKL pseudokinase domain bound to compound 2

Structural highlights

6o5z is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.285Å
Ligands:	EDO, LN4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

Publication Abstract from PubMed

Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).

Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway.,Pierotti CL, Tanzer MC, Jacobsen AV, Hildebrand JM, Garnier JM, Sharma P, Lucet IS, Cowan AD, Kersten WJA, Luo MX, Liang LY, Fitzgibbon C, Garnish SE, Hempel A, Nachbur U, Huang DCS, Czabotar PE, Silke J, van Delft MF, Murphy JM, Lessene G ACS Chem Biol. 2020 Oct 16;15(10):2702-2713. doi: 10.1021/acschembio.0c00482., Epub 2020 Sep 22. PMID:32902249^[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
↑ Pierotti CL, Tanzer MC, Jacobsen AV, Hildebrand JM, Garnier JM, Sharma P, Lucet IS, Cowan AD, Kersten WJA, Luo MX, Liang LY, Fitzgibbon C, Garnish SE, Hempel A, Nachbur U, Huang DCS, Czabotar PE, Silke J, van Delft MF, Murphy JM, Lessene G. Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway. ACS Chem Biol. 2020 Oct 16;15(10):2702-2713. doi: 10.1021/acschembio.0c00482., Epub 2020 Sep 22. PMID:32902249 doi:https://dx.doi.org/10.1021/acschembio.0c00482

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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] Pierotti CL, Tanzer MC, Jacobsen AV, Hildebrand JM, Garnier JM, Sharma P, Lucet IS, Cowan AD, Kersten WJA, Luo MX, Liang LY, Fitzgibbon C, Garnish SE, Hempel A, Nachbur U, Huang DCS, Czabotar PE, Silke J, van Delft MF, Murphy JM, Lessene G. Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway. ACS Chem Biol. 2020 Oct 16;15(10):2702-2713. doi: 10.1021/acschembio.0c00482., Epub 2020 Sep 22. PMID:32902249 doi:https://dx.doi.org/10.1021/acschembio.0c00482

[1]

[2]

6o5z

Crystal Structure of the human MLKL pseudokinase domain bound to compound 2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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