2V00

X-ray crystal structure of endothiapepsin complexed with compound 1

2V00 の概要

• エントリーDOI: 10.2210/pdb2v00/pdb
• 関連するPDBエントリー: 1E5O 1E80 1E81 1E82 1EED 1ENT 1GKT 1GVT 1GVU 1GVV 1GVW 1GVX 1OD1 1OEW 1OEX
• 分子名称: ENDOTHIAPEPSIN, GLYCEROL, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: fragment hit, b- secretase, endothiapepsin, bace, zymogen, protease, hydrolase, isocytosine, alzheimer's disease, fragment-based lead generation, aspartyl protease, surrogate protein
• 由来する生物種: CRYPHONECTRIA PARASITICA (CHESTNUT BLIGHT FUNGUS)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34423.48

構造登録者

Geschwindner, S.,Olsson, L.L.,Deinum, J.,Albert, J.S.,Edwards, P.D.,De Beer, T.,Folmer, R.H.A. (登録日: 2007-05-03, 公開日: 2007-12-04, 最終更新日: 2024-11-13)

主引用文献

Geschwindner, S.,Olsson, L.L.,Albert, J.S.,Deinum, J.,Edwards, P.D.,De Beer, T.,Folmer, R.H.A.
Discovery of a Novel Warhead Against Beta-Secretase Through Fragment-Based Lead Generation.
J.Med.Chem., 50:5903-, 2007

PubMed Abstract: Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1.

PubMed: 17985861
DOI: 10.1021/JM070825K

実験手法

X-RAY DIFFRACTION (1.55 Å)