4EHF

Allosteric Modulation of Caspase-3 through Mutagenesis

4EHF の概要

• エントリーDOI: 10.2210/pdb4ehf/pdb
• 関連するPDBエントリー: 4EHA 4EHD 4EHH 4EHK 4EHL 4EHN
• 関連するBIRD辞書のPRD_ID: PRD_000238
• 分子名称: Caspase-3, ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR (3 entities in total)
• 機能のキーワード: caspase, apoptosis, allosteric inhibition, protein ensembles, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 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: 32165.87

構造登録者

Walters, J.,Schipper, J.L.,Swartz, P.D.,Mattos, C.,Clark, A.C. (登録日: 2012-04-02, 公開日: 2012-06-06, 最終更新日: 2024-10-16)

主引用文献

Walters, J.,Schipper, J.L.,Swartz, P.,Mattos, C.,Clark, A.C.
Allosteric modulation of caspase 3 through mutagenesis.
Biosci.Rep., 32:401-411, 2012

PubMed Abstract: A mutation in the allosteric site of the caspase 3 dimer interface of Val266 to histidine abolishes activity of the enzyme, and models predict that the mutation mimics the action of small molecule allosteric inhibitors by preventing formation of the active site. Mutations were coupled to His266 at two sites in the interface, E124A and Y197C. We present results from X-ray crystallography, enzymatic activity and molecular dynamics simulations for seven proteins, consisting of single, double and triple mutants. The results demonstrate that considering allosteric inhibition of caspase 3 as a shift between discrete 'off-state' or 'on-state' conformations is insufficient. Although His266 is accommodated in the interface, the structural defects are propagated to the active site through a helix on the protein surface. A more comprehensive view of allosteric regulation of caspase 3 requires the representation of an ensemble of inactive states and shows that subtle structural changes lead to the population of the inactive ensemble.

PubMed: 22607239
DOI: 10.1042/BSR20120037

実験手法

X-RAY DIFFRACTION (1.655 Å)