1RHM

CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A NICOTINIC ACID ALDEHYDE INHIBITOR

1RHM の概要

• エントリーDOI: 10.2210/pdb1rhm/pdb
• 関連するPDBエントリー: 1PAU 1RHJ 1RHK 1RHQ 1RHR 1RHU
• 分子名称: CASP-3, 4-[5-(2-CARBOXY-1-FORMYL-ETHYLCARBAMOYL)-PYRIDIN-3-YL]-BENZOIC ACID, ... (4 entities in total)
• 機能のキーワード: cysteine protease, caspase-3, apopain, cpp32, yama, complex (protease-inhibitor), hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: P42574 P42574
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 57785.62

構造登録者

Becker, J.W.,Rotonda, J.,Soisson, S.M. (登録日: 2003-11-14, 公開日: 2004-05-11, 最終更新日: 2024-10-30)

主引用文献

Becker, J.W.,Rotonda, J.,Soisson, S.M.,Aspiotis, R.,Bayly, C.,Francoeur, S.,Gallant, M.,Garcia-Calvo, M.,Giroux, A.,Grimm, E.,Han, Y.,McKay, D.,Nicholson, D.W.,Peterson, E.,Renaud, J.,Roy, S.,Thornberry, N.,Zamboni, R.
Reducing the Peptidyl Features of Caspase-3 Inhibitors: A Structural Analysis.
J.Med.Chem., 47:2466-2474, 2004

PubMed Abstract: Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency.

PubMed: 15115390
DOI: 10.1021/jm0305523

実験手法

X-RAY DIFFRACTION (2.5 Å)