4KE0

Crystal structure of BACE1 in complex with hydroxyethylamine-macrocyclic inhibitor 13

4KE0 の概要

• エントリーDOI: 10.2210/pdb4ke0/pdb
• 関連するPDBエントリー: 4K8S 4K9H 4KE1
• 分子名称: Beta-secretase 1, (3S)-3-[(1R)-2-{[(4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]amino}-1-hydroxyethyl]-4-azabicyclo[10.3.1]hexadeca-1(16),12,14-trien-5-one, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: alzheimer's disease, aspartic protease, amyloid precursor protein (app), hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 3
• 化学式量合計: 139219.62

構造登録者

Whittington, D.A.,Long, A.M.,Li, V. (登録日: 2013-04-25, 公開日: 2013-07-03, 最終更新日: 2024-11-20)

主引用文献

Pennington, L.D.,Whittington, D.A.,Bartberger, M.D.,Jordan, S.R.,Monenschein, H.,Nguyen, T.T.,Yang, B.H.,Xue, Q.M.,Vounatsos, F.,Wahl, R.C.,Chen, K.,Wood, S.,Citron, M.,Patel, V.F.,Hitchcock, S.A.,Zhong, W.
Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.
Bioorg.Med.Chem.Lett., 23:4459-4464, 2013

PubMed Abstract: We describe a systematic study of how macrocyclization in the P₁-P₃ region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.

PubMed: 23769639
DOI: 10.1016/j.bmcl.2013.05.028

実験手法

X-RAY DIFFRACTION (2.3 Å)