1YM2

Crystal structure of human beta secretase complexed with NVP-AUR200

1YM2 の概要

• エントリーDOI: 10.2210/pdb1ym2/pdb
• 関連するPDBエントリー: 1YM4
• 関連するBIRD辞書のPRD_ID: PRD_000291
• 分子名称: Beta-secretase 1, NVP-AUR200 INHIBITOR (3 entities in total)
• 機能のキーワード: beta-secretase, memapsin2, alzheimer's disease, aspartic protease, hydrolase, 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: 6
• 化学式量合計: 136335.84

構造登録者

Hanessian, S.,Yun, H.,Hou, Y.,Yang, G.,Bayrakdarian, M.,Therrien, E.,Moitessier, N.,Roggo, S.,Veenstra, S. (登録日: 2005-01-20, 公開日: 2006-01-17, 最終更新日: 2024-10-23)

主引用文献

Hanessian, S.,Yun, H.,Hou, Y.,Yang, G.,Bayrakdarian, M.,Therrien, E.,Moitessier, N.,Roggo, S.,Veenstra, S.,Tintelnot-Blomley, M.,Rondeau, J.M.,Ostermeier, C.,Strauss, A.,Ramage, P.,Paganetti, P.,Neumann, U.,Betschart, C.
Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics
J.Med.Chem., 48:5175-5190, 2005

PubMed Abstract: Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.

PubMed: 16078837
DOI: 10.1021/jm050142+

実験手法

X-RAY DIFFRACTION (2.05 Å)