8eg6
huCaspase-6 in complex with inhibitor 2ahuCaspase-6 in complex with inhibitor 2a
Structural highlights
FunctionCASP6_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. Publication Abstract from PubMedCaspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.,Van Horn KS, Wang D, Medina-Cleghorn D, Lee PS, Bryant C, Altobelli C, Jaishankar P, Leung KK, Ng RA, Ambrose AJ, Tang Y, Arkin MR, Renslo AR J Am Chem Soc. 2023 May 10;145(18):10015-10021. doi: 10.1021/jacs.2c12240. Epub , 2023 Apr 27. PMID:37104712[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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