2C2Z

Crystal structure of caspase-8 in complex with aza-peptide Michael acceptor inhibitor

2C2Z の概要

• エントリーDOI: 10.2210/pdb2c2z/pdb
• 関連するPDBエントリー: 1F9E 1I4E 1QDU 1QTN 2FUN
• 関連するBIRD辞書のPRD_ID: PRD_000336
• 分子名称: CASPASE-8 P18 SUBUNIT, CASPASE-8 P10 SUBUNIT, AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL) -14-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL] -11-[(1R)-1-HYDROXYETHYL]-5-(2-METHYLPROPYL)-3,6,9,12-TETRAOXO -1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID, ... (5 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, apoptosis, cysteine-protease, ice, thiol protease, zymogen, cpp32, yama, aza-peptide, michael acceptor, aza-asp, clan cd, hydrolase/hydrolase inhibitor
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Cytoplasm: Q14790 2C2Z
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 31219.93

構造登録者

Ganesan, R.,Jelakovic, S.,Ekici, O.D.,Li, Z.Z.,James, K.E.,Asgian, J.L.,Campbell, A.J.,Mikolajczyk, J.,Salvesen, G.S.,Powers, J.C.,Gruetter, M.G. (登録日: 2005-10-02, 公開日: 2006-09-20, 最終更新日: 2025-04-09)

主引用文献

Ekici, O.D.,Li, Z.Z.,Campbell, A.J.,James, K.E.,Asgian, J.L.,Mikolajczyk, J.,Salvesen, G.S.,Ganesan, R.,Jelakovic, S.,Grutter, M.G.,Powers, J.C.
Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Selective and Potent Inhibitors of Caspases-2, -3, -6, -7, -8, -9, and - 10.
J.Med.Chem., 49:5728-, 2006

PubMed Abstract: Aza-peptide Michael acceptors are a novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 10(6) M(-1) s(-1). The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH(2)-1-Naphth)(2) is the most potent compound and it inhibits caspase-3 with a k(2) value of 5620000 M(-1) s(-1). The inhibitor 18t is 13700, 190, 6.4, 594, 37500, and 173-fold more selective for caspase-3 over caspases-2, -6, -7, -8, -9, and -10, respectively. Aza-peptide Michael acceptors designed with caspase specific sequences are selective and do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpains. High-resolution crystal structures of caspase-3 and caspase-8 in complex with aza-peptide Michael acceptor inhibitors demonstrate the nucleophilic attack on C2 and provide insight into the selectivity and potency of the inhibitors with respect to the P1' moiety.

PubMed: 16970398
DOI: 10.1021/JM0601405

実験手法

X-RAY DIFFRACTION (1.95 Å)