4FDL

Crystal structure of Caspase-7

Summary for 4FDL

• Entry DOI: 10.2210/pdb4fdl/pdb
• Related: 4FEA
• Descriptor: Caspase-7 (2 entities in total)
• Functional Keywords: cysteine protease, central cavity, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P55210
• Total number of polymer chains: 2
• Total formula weight: 69132.20

Authors

Kabaleeswaran, V. (deposition date: 2012-05-28, release date: 2012-08-01, Last modification date: 2023-09-13)

Primary citation

Feldman, T.,Kabaleeswaran, V.,Jang, S.B.,Antczak, C.,Djaballah, H.,Wu, H.,Jiang, X.
A class of allosteric caspase inhibitors identified by high-throughput screening.
Mol.Cell, 47:585-595, 2012

PubMed Abstract: Caspase inhibition is a promising approach for treating multiple diseases. Using a reconstituted assay and high-throughput screening, we identified a group of nonpeptide caspase inhibitors. These inhibitors share common chemical scaffolds, suggesting the same mechanism of action. They can inhibit apoptosis in various cell types induced by multiple stimuli; they can also inhibit caspase-1-mediated interleukin generation in macrophages, indicating potential anti-inflammatory application. While these compounds inhibit all the tested caspases, kinetic analysis indicates they do not compete for the catalytic sites of the enzymes. The cocrystal structure of one of these compounds with caspase-7 reveals that it binds to the dimerization interface of the caspase, another common structural element shared by all active caspases. Consistently, biochemical analysis demonstrates that the compound abates caspase-8 dimerization. Based on these kinetic, biochemical, and structural analyses, we suggest that these compounds are allosteric caspase inhibitors that function through binding to the dimerization interface of caspases.

PubMed: 22795132
DOI: 10.1016/j.molcel.2012.06.007

Experimental method

X-RAY DIFFRACTION (2.801 Å)