4TRW

Structure of BACE1 complex with a syn-HEA-type inhibitor

4TRW の概要

• エントリーDOI: 10.2210/pdb4trw/pdb
• 関連するPDBエントリー: 4TRY 4TRZ
• 関連するBIRD辞書のPRD_ID: PRD_002103
• 分子名称: Beta-secretase 1, L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide (3 entities in total)
• 機能のキーワード: hydrase proteinase converting, designed inhibitor, hydrase-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 132203.34

構造登録者

Akaji, K.,Teruya, K.,Akiyama, T.,Sanjho, A.,Yamashita, E.,Nakagawa, A. (登録日: 2014-06-18, 公開日: 2015-07-01, 最終更新日: 2024-10-30)

主引用文献

Hattori, Y.,Kobayashi, K.,Deguchi, A.,Nohara, Y.,Akiyama, T.,Teruya, K.,Sanjoh, A.,Nakagawa, A.,Yamashita, E.,Akaji, K.
Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors
Bioorg.Med.Chem., 23:5626-5640, 2015

PubMed Abstract: A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4 to P1' sites (Glu-Ile-Thi-Thi(*)Nva; (*)denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity; anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereas anti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein-ligand interactions, especially at the prime sites.

PubMed: 26264846
DOI: 10.1016/j.bmc.2015.07.023

実験手法

X-RAY DIFFRACTION (2.85 Å)