3DEH

Crystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-trione Derivative Inhibitors

3DEH の概要

• エントリーDOI: 10.2210/pdb3deh/pdb
• 関連するPDBエントリー: 3DEI 3DEJ 3DEK
• 分子名称: Caspase-3, isoquinoline-1,3,4(2H)-trione (3 entities in total)
• 機能のキーワード: caspase-3, isoquinoline-1, 3, 4-trione derivatives, inactivation, protein-inhibitor complex, cytoplasm, hydrolase, apoptosis, phosphoprotein, polymorphism, protease, s-nitrosylation, thiol protease, zymogen
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P42574
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 114441.14

構造登録者

Wu, J.,Du, J.,Li, J.,Ding, J. (登録日: 2008-06-10, 公開日: 2008-09-02, 最終更新日: 2023-11-15)

主引用文献

Du, J.-Q.,Wu, J.,Zhang, H.-J.,Zhang, Y.-H.,Qiu, B.-Y.,Wu, F.,Chen, Y.-H.,Li, J.-Y.,Nan, F.-J.,Ding, J.-P.,Li, J.
Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species
J.Biol.Chem., 283:30205-30215, 2008

PubMed Abstract: Caspase-3 is an attractive therapeutic target for treatment of diseases involving disregulated apoptosis. We report here the mechanism of caspase-3 inactivation by isoquinoline-1,3,4-trione derivatives. Kinetic analysis indicates the compounds can irreversibly inactivate caspase-3 in a 1,4-dithiothreitol (DTT)- and oxygen-dependent manner, implying that a redox cycle might take place in the inactivation process. Reactive oxygen species detection experiments using a chemical indicator, together with electron spin resonance measurement, suggest that ROS can be generated by reaction of isoquinoline-1,3,4-trione derivatives with DTT. Oxygen-free radical scavenger catalase and superoxide dismutase eliciting the inactivation of caspase-3 by the inhibitors confirm that ROS mediates the inactivation process. Crystal structures of caspase-3 in complexes with isoquinoline-1,3,4-trione derivatives show that the catalytic cysteine is oxidized to sulfonic acid (-SO(3)H) and isoquinoline-1,3,4-trione derivatives are bound at the dimer interface of caspase-3. Further mutagenesis study shows that the binding of the inhibitors with caspase-3 appears to be nonspecific. Isoquinoline-1,3,4-trione derivative-catalyzed caspase-3 inactivation could also be observed when DTT is substituted with dihydrolipoic acid, which exists widely in cells and might play an important role in the in vivo inactivation process in which the inhibitors inactivate caspase-3 in cells and then prevent the cells from apoptosis. These results provide valuable information for further development of small molecular inhibitors against caspase-3 or other oxidation-sensitive proteins.

PubMed: 18768468
DOI: 10.1074/jbc.M803347200

実験手法

X-RAY DIFFRACTION (2.5 Å)