4N7M

Tailoring Small Molecules for an Allosteric Site on Procaspase-6

4N7M の概要

• エントリーDOI: 10.2210/pdb4n7m/pdb
• 関連するPDBエントリー: 4N5D 4N6G 4N7J 4NBK 4NBL 4NBN
• 分子名称: Caspase-6, 3-(pyrrolidin-1-yl)isoquinolin-1(2H)-one, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: procaspse-6, caspase-6 zymogen, allosteric, structure based drug design, cysteine protease, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P55212
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65316.83

構造登録者

Murray, J.M.,Steffek, M. (登録日: 2013-10-15, 公開日: 2013-12-18, 最終更新日: 2024-02-28)

主引用文献

Murray, J.,Giannetti, A.M.,Steffek, M.,Gibbons, P.,Hearn, B.R.,Cohen, F.,Tam, C.,Pozniak, C.,Bravo, B.,Lewcock, J.,Jaishankar, P.,Ly, C.Q.,Zhao, X.,Tang, Y.,Chugha, P.,Arkin, M.R.,Flygare, J.,Renslo, A.R.
Tailoring small molecules for an allosteric site on procaspase-6.
Chemmedchem, 9:73-77, 2014

PubMed Abstract: Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules.

PubMed: 24259468
DOI: 10.1002/cmdc.201300424

実験手法

X-RAY DIFFRACTION (2.125 Å)