4JJE

Caspase-3 specific unnatural amino acid peptides

4JJE の概要

• エントリーDOI: 10.2210/pdb4jje/pdb
• 関連するPDBエントリー: 4JJ7 4JJ8
• 関連するBIRD辞書のPRD_ID: PRD_000925
• 分子名称: Caspase-3, Caspase inhibitor (3 entities in total)
• 機能のキーワード: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P42574
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30425.63

構造登録者

Vickers, C.J.,Gonzalez-Paez, G.E.,Wolan, D.W. (登録日: 2013-03-07, 公開日: 2013-06-12, 最終更新日: 2023-11-15)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.481 Å)