8EG6

huCaspase-6 in complex with inhibitor 2a

8EG6 の概要

• エントリーDOI: 10.2210/pdb8eg6/pdb
• 分子名称: Caspase-6 subunit p18, Caspase-6 subunit p11, CHLORIDE ION, ... (7 entities in total)
• 機能のキーワード: cysteine covalent inhibitor competitive inhibitor protease, apoptosis, protease-protease inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 121704.67

構造登録者

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. (登録日: 2022-09-11, 公開日: 2023-05-10, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.82 Å)