4GID

Structure of beta-secretase complexed with inhibitor

4GID の概要

• エントリーDOI: 10.2210/pdb4gid/pdb
• 関連するPDBエントリー: 1fkn 2g94 2vkm
• 分子名称: Beta-secretase 1, N-[(2S)-1-({(2S,3R)-3-hydroxy-1-[(2-methylpropyl)amino]-1-oxobutan-2-yl}amino)-3-phenylpropan-2-yl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide, L-PROLINAMIDE, ... (4 entities in total)
• 機能のキーワード: aspartic protease, beta secretase, app, bace, a-beta, protease, memapsin, alzheimer, drug design, 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: 4
• 化学式量合計: 176142.97

構造登録者

Ghosh, A.,Tang, J.,Venkateswara, R.K.,Yadav, N.,Anderson, D.,Gavande, N.,Huang, X.,Terzyan, S. (登録日: 2012-08-08, 公開日: 2012-10-10, 最終更新日: 2023-09-13)

主引用文献

Ghosh, A.K.,Venkateswara Rao, K.,Yadav, N.D.,Anderson, D.D.,Gavande, N.,Huang, X.,Terzyan, S.,Tang, J.
Structure-based design of highly selective beta-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
J.Med.Chem., 55:9195-9207, 2012

PubMed Abstract: The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.

PubMed: 22954357
DOI: 10.1021/jm3008823

実験手法

X-RAY DIFFRACTION (2 Å)