1NMS

Caspase-3 tethered to irreversible inhibitor

1NMS の概要

• エントリーDOI: 10.2210/pdb1nms/pdb
• 関連するPDBエントリー: 1NME 1NMQ
• 分子名称: Caspase-3, 5-[4-(1-CARBOXYMETHYL-2-OXO-PROPYLCARBAMOYL)-BENZYLSULFAMOYL]-2-HYDROXY-BENZOIC ACID (3 entities in total)
• 機能のキーワード: caspase-3, tether, irreversible, inhibitor, apoptosis, hydrolase
• 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: 57965.89

構造登録者

Erlanson, D.A.,Lam, J.,Wiesmann, C.,Luong, T.N.,Simmons, R.L.,DeLano, W.L.,Choong, I.C.,Flanagan, W.M.,Lee, D.,O'Brian, T. (登録日: 2003-01-10, 公開日: 2003-03-11, 最終更新日: 2023-08-16)

主引用文献

Erlanson, D.A.,Lam, J.W.,Wiesmann, C.,Luong, T.N.,Simmons, R.L.,DeLano, W.L.,Choong, I.C.,Burdett, M.T.,Flanagan, W.M.,Lee, D.,Gordon, E.M.,O'Brien, T.
In situ assembly of enzyme inhibitors using extended tethering.
Nat.Biotechnol., 21:308-314, 2003

PubMed Abstract: Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.

PubMed: 12563278
DOI: 10.1038/nbt786

実験手法

X-RAY DIFFRACTION (1.7 Å)