5MCQ

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH ACTIVE SITE AND EXOSITE BINDING PEPTIDE INHIBITOR

5MCQ の概要

• エントリーDOI: 10.2210/pdb5mcq/pdb
• 関連するPDBエントリー: 5MBW 5MCO
• 分子名称: Beta-secretase 1, BACE-1 ACTIVE AND EXOSITE BINDING INHIBITOR, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase, exosite
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48094.91

構造登録者

Kuglstatter, A.,Stihle, M.,Benz, J. (登録日: 2016-11-10, 公開日: 2017-09-27, 最終更新日: 2024-10-23)

主引用文献

Ruderisch, N.,Schlatter, D.,Kuglstatter, A.,Guba, W.,Huber, S.,Cusulin, C.,Benz, J.,Rufer, A.C.,Hoernschemeyer, J.,Schweitzer, C.,Bulau, T.,Gartner, A.,Hoffmann, E.,Niewoehner, J.,Patsch, C.,Baumann, K.,Loetscher, H.,Kitas, E.,Freskgard, P.O.
Potent and Selective BACE-1 Peptide Inhibitors Lower Brain A beta Levels Mediated by Brain Shuttle Transport.
EBioMedicine, 24:76-92, 2017

PubMed Abstract: Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

PubMed: 28923680
DOI: 10.1016/j.ebiom.2017.09.004

実験手法

X-RAY DIFFRACTION (1.82 Å)