2OHS

X-ray crystal structure of beta secretase complexed with compound 6b

2OHS の概要

• エントリーDOI: 10.2210/pdb2ohs/pdb
• 関連するPDBエントリー: 2OF0 2OHK 2OHL 2OHM 2OHN 2OHP 2OHQ 2OHR 2OHT 2OHU
• 分子名称: Beta-secretase 1, IODIDE ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: alternative splicing, alzheimer's disease, aspartic protease, aspartyl protease, base, beta-secretase, glycoprotein, hydrolase, memapsin 2, transmembrane, zymogen
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45479.70

構造登録者

Patel, S. (登録日: 2007-01-10, 公開日: 2007-03-13, 最終更新日: 2024-10-30)

主引用文献

Congreve, M.,Aharony, D.,Albert, J.,Callaghan, O.,Campbell, J.,Carr, R.A.,Chessari, G.,Cowan, S.,Edwards, P.D.,Frederickson, M.,McMenamin, R.,Murray, C.W.,Patel, S.,Wallis, N.
Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase.
J.Med.Chem., 50:1124-1132, 2007

PubMed Abstract: Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 microM) and 6c (IC50 = 24 microM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).

PubMed: 17315857
DOI: 10.1021/jm061197u

実験手法

X-RAY DIFFRACTION (2.45 Å)