2F3F

Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor

2F3F の概要

• エントリーDOI: 10.2210/pdb2f3f/pdb
• 関連するPDBエントリー: 2F3E
• 分子名称: Beta-secretase 1, (2R,4S)-N-BUTYL-4-HYDROXY-2-METHYL- 4-((E)-(4AS,12R,15S,17AS)-15-METHYL -14,17-DIOXO-2,3,4,4A,6,9,11,12,13, 14,15,16,17,17A-TETRADECAHYDRO-1H-5 ,10-DITHIA-1,13,16-TRIAZA-BENZOCYCL OPENTADECEN-12-YL)-BUTYRAMIDE (3 entities in total)
• 機能のキーワード: beta-secretase, memapsin2, alzheimer's disease, aspartic protease, macrocyclic peptidomimetic inhibitor, hydrolase
• 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: 135876.24

構造登録者

Rondeau, J.-M. (登録日: 2005-11-21, 公開日: 2006-09-05, 最終更新日: 2024-10-16)

主引用文献

Hanessian, S.,Yang, G.,Rondeau, J.-M.,Neumann, U.,Betschart, C.,Tintelnot-Blomley, M.
Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE).
J.Med.Chem., 49:4544-4567, 2006

PubMed Abstract: Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.

PubMed: 16854060
DOI: 10.1021/jm060154a

実験手法

X-RAY DIFFRACTION (2.3 Å)