4JJ8

Caspase-3 specific unnatural amino acid peptides

Summary for 4JJ8

• Entry DOI: 10.2210/pdb4jj8/pdb
• Related: 1F1J 2QL5 3IBC 4JJ7 4JJE
• Related PRD ID: PRD_000925
• Descriptor: Caspase-7, Caspase Inhibitor (3 entities in total)
• Functional Keywords: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P55210
• Total number of polymer chains: 4
• Total formula weight: 59960.04

Authors

Vickers, C.J.,Gonzalez-Paez, G.E.,Wolan, D.W. (deposition date: 2013-03-07, release date: 2013-06-12, Last modification date: 2023-11-15)

Primary citation

Vickers, C.J.,Gonzalez-Paez, G.E.,Wolan, D.W.
Selective Detection of Caspase-3 versus Caspase-7 Using Activity-Based Probes with Key Unnatural Amino Acids.
Acs Chem.Biol., 8:1558-1566, 2013

PubMed Abstract: Caspases are required for essential biological functions, most notably apoptosis and pyroptosis, but also cytokine production, cell proliferation, and differentiation. One of the most well studied members of this cysteine protease family includes executioner caspase-3, which plays a central role in cell apoptosis and differentiation. Unfortunately, there exists a dearth of chemical tools to selectively monitor caspase-3 activity under complex cellular and in vivo conditions due to its close homology with executioner caspase-7. Commercially available activity-based probes and substrates rely on the canonical DEVD tetrapeptide sequence, which both caspases-3 and -7 recognize with similar affinity, and thus the individual contributions of caspase-3 and/or -7 toward important cellular processes are irresolvable. Here, we analyzed a variety of permutations of the DEVD peptide sequence in order to discover peptides with biased activity and recognition of caspase-3 versus caspases-6, -7, -8, and -9. Through this study, we identify fluorescent and biotinylated probes capable of selective detection of caspase-3 using key unnatural amino acids. Likewise, we determined the X-ray crystal structures of caspases-3, -7, and -8 in complex with our lead peptide inhibitor to elucidate the binding mechanism and active site interactions that promote the selective recognition of caspase-3 over other highly homologous caspase family members.

PubMed: 23614665
DOI: 10.1021/cb400209w

Experimental method

X-RAY DIFFRACTION (2.937 Å)