3R5K

A designed redox-controlled caspase-7

Summary for 3R5K

• Entry DOI: 10.2210/pdb3r5k/pdb
• Related: 1F1J 1GQF 1I4O 1I51 1K86 1K88 1KMC 1SHJ 1SHL 2QL5 2QL7 2QL9 2QLB 2QLF 2QLJ 3EDR 3H1P 3IBC 3IBF
• Descriptor: Caspase-7, FORMIC ACID (3 entities in total)
• Functional Keywords: apoptosis, hydrolase, protease, thiol protease, zymogen, caspase, cystine aspartate protease
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P55210
• Total number of polymer chains: 2
• Total formula weight: 71188.24

Authors

Witkowski, W.A.,Hardy, J.A. (deposition date: 2011-03-18, release date: 2011-06-29, Last modification date: 2023-09-13)

Primary citation

Witkowski, W.A.,Hardy, J.A.
A designed redox-controlled caspase.
Protein Sci., 20:1421-1431, 2011

PubMed Abstract: Caspases are a powerful class of cysteine proteases. Introduction of activated caspases in healthy or cancerous cells results in induction of apoptotic cell death. In this study, we have designed and characterized a version of caspase-7 that can be inactivated under oxidizing extracellular conditions and then reactivated under reducing intracellular conditions. This version of caspase-7 is allosterically inactivated when two of the substrate-binding loops are locked together via an engineered disulfide. When this disulfide is reduced, the protein regains its full function. The inactive loop-locked version of caspase-7 can be readily observed by immunoblotting and mass spectrometry. The reduced and reactivated form of the enzyme observed crystallographically is the first caspase-7 structure in which the substrate-binding groove is properly ordered even in the absence of an active-site ligand. In the reactivated structure, the catalytic-dyad cysteine-histidine are positioned 3.5 Å apart in an orientation that is capable of supporting catalysis. This redox-controlled version of caspase-7 is particularly well suited for targeted cell death in concert with redox-triggered delivery vehicles.

PubMed: 21674661
DOI: 10.1002/pro.673

Experimental method

X-RAY DIFFRACTION (2.86 Å)