4EJF

Allosteric peptides that bind to a caspase zymogen and mediate caspase tetramerization

Summary for 4EJF

• Entry DOI: 10.2210/pdb4ejf/pdb
• Descriptor: Caspase-6, phage-derived peptide 419, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: caspase-6, zymogen, c163a, caspase, protease, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P55212
• Total number of polymer chains: 8
• Total formula weight: 137342.77

Authors

Murray, J.M. (deposition date: 2012-04-06, release date: 2012-06-20, Last modification date: 2024-11-27)

Primary citation

Stanger, K.,Steffek, M.,Zhou, L.,Pozniak, C.D.,Quan, C.,Franke, Y.,Tom, J.,Tam, C.,Elliott, J.M.,Lewcock, J.W.,Zhang, Y.,Murray, J.,Hannoush, R.N.
Allosteric peptides bind a caspase zymogen and mediate caspase tetramerization.
Nat.Chem.Biol., 8:655-660, 2012

PubMed Abstract: The caspases are a family of cytosolic proteases with essential roles in inflammation and apoptosis. Drug discovery efforts have focused on developing molecules directed against the active sites of caspases, but this approach has proved challenging and has not yielded any approved therapeutics. Here we describe a new strategy for generating inhibitors of caspase-6, a potential therapeutic target in neurodegenerative disorders, by screening against its zymogen form. Using phage display to discover molecules that bind the zymogen, we report the identification of a peptide that specifically impairs the function of caspase-6 in vitro and in neuronal cells. Remarkably, the peptide binds at a tetramerization interface that is uniquely present in zymogen caspase-6, rather than binding into the active site, and acts via a new allosteric mechanism that promotes caspase tetramerization. Our data illustrate that screening against the zymogen holds promise as an approach for targeting caspases in drug discovery.

PubMed: 22683611
DOI: 10.1038/nchembio.967

Experimental method

X-RAY DIFFRACTION (2.6465 Å)