4JR2

Human procaspase-7/caspase-7 heterodimer bound to Ac-DEVD-CMK

4JR2 の概要

• エントリーDOI: 10.2210/pdb4jr2/pdb
• 関連するPDBエントリー: 4JQY 4JQZ 4JR0 4JR1
• 関連するBIRD辞書のPRD_ID: PRD_000238
• 分子名称: Procaspase-7, Ac-DEVD-CMK, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: protease, proenzyme, protein-peptide complex, irreversible inhibitor, activity based probe, caspase, apoptosis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P55210
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 57771.13

構造登録者

Thomsen, N.D.,Wells, J.A. (登録日: 2013-03-20, 公開日: 2013-05-08, 最終更新日: 2024-11-06)

主引用文献

Thomsen, N.D.,Koerber, J.T.,Wells, J.A.
Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.
Proc.Natl.Acad.Sci.USA, 110:8477-8482, 2013

PubMed Abstract: Procaspase-3 (P3) and procaspase-7 (P7) are activated through proteolytic maturation to form caspase-3 (C3) and caspase-7 (C7), respectively, which serve overlapping but nonredundant roles as the executioners of apoptosis in humans. However, it is unclear if differences in P3 and P7 maturation mechanisms underlie their unique biological functions, as the structure of P3 remains unknown. Here, we report structures of P3 in a catalytically inactive conformation, structures of P3 and P7 bound to covalent peptide inhibitors that reveal the active conformation of the zymogens, and the structure of a partially matured C7:P7 heterodimer. Along with a biochemical analysis, we show that P3 is catalytically inactive and matures through a symmetric all-or-nothing process. In contrast, P7 contains latent catalytic activity and matures through an asymmetric and tiered mechanism, suggesting a lower threshold for activation. Finally, we use our structures to design a selection strategy for conformation specific antibody fragments that stimulate procaspase activity, showing that executioner procaspase conformational equilibrium can be rationally modulated. Our studies provide a structural framework that may help to explain the unique roles of these important proapoptotic enzymes, and suggest general strategies for the discovery of proenzyme activators.

PubMed: 23650375
DOI: 10.1073/pnas.1306759110

実験手法

X-RAY DIFFRACTION (1.65 Å)