8EG5

huCaspase-6 in complex with inhibitor 3a

Summary for 8EG5

• Entry DOI: 10.2210/pdb8eg5/pdb
• Descriptor: Caspase-6 subunit p18, Caspase-6 subunit p11, (3R,5S)-1-(ethanesulfonyl)-5-phenyl-N-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxamide (bound form), ... (5 entities in total)
• Functional Keywords: cysteine covalent inhibitor competitive inhibitor protease, apoptosis, protease-protease inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 121229.13

Authors

Zhao, Y.,Fan, P.,Liu, J.,Wang, Y.,Van Horn, K.,Wang, D.,Medina-Cleghorn, D.,Lee, P.,Bryant, C.,Altobelli, C.,Jaishankar, P.,Ng, R.A.,Ambrose, A.J.,Tang, Y.,Arkin, M.R.,Renslo, A.R. (deposition date: 2022-09-11, release date: 2023-05-10, Last modification date: 2024-10-16)

Primary citation

Van Horn, K.S.,Wang, D.,Medina-Cleghorn, D.,Lee, P.S.,Bryant, C.,Altobelli, C.,Jaishankar, P.,Leung, K.K.,Ng, R.A.,Ambrose, A.J.,Tang, Y.,Arkin, M.R.,Renslo, A.R.
Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.
J.Am.Chem.Soc., 145:10015-10021, 2023

PubMed Abstract: Caspases 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 () and chemoproteomic probes () 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.

PubMed: 37104712
DOI: 10.1021/jacs.2c12240

Experimental method

X-RAY DIFFRACTION (2.14 Å)