2OHL

X-ray crystal structure of beta secretase complexed with 2-aminoquinoline

2OHL の概要

• エントリーDOI: 10.2210/pdb2ohl/pdb
• 関連するPDBエントリー: 2OF0 2OHK 2OHM 2OHN 2OHP 2OHQ 2OHR 2OHS 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: 45444.41

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

Murray, C.W.,Callaghan, O.,Chessari, G.,Cleasby, A.,Congreve, M.,Frederickson, M.,Hartshorn, M.J.,McMenamin, R.,Patel, S.,Wallis, N.
Application of fragment screening by X-ray crystallography to beta-Secretase.
J.Med.Chem., 50:1116-1123, 2007

PubMed Abstract: This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.

PubMed: 17315856
DOI: 10.1021/jm0611962

実験手法

X-RAY DIFFRACTION (2.65 Å)