3L5D

Structure of BACE Bound to SCH723873

3L5D の概要

• エントリーDOI: 10.2210/pdb3l5d/pdb
• 関連するPDBエントリー: 3L58 3L59 3L5B 3L5C 3L5E 3L5F
• 分子名称: Beta-secretase 1, D(-)-TARTARIC ACID, 1-butyl-3-(4-{[(2Z,4R)-2-imino-4-methyl-4-(2-methylpropyl)-5-oxoimidazolidin-1-yl]methyl}benzyl)urea, ... (4 entities in total)
• 機能のキーワード: bace1, alzheimers, alternative splicing, aspartyl protease, disulfide bond, endoplasmic reticulum, endosome, glycoprotein, golgi apparatus, hydrolase, membrane, polymorphism, protease, transmembrane, zymogen
• 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: 2
• 化学式量合計: 93725.15

構造登録者

Strickland, C.,Zhu, Z. (登録日: 2009-12-21, 公開日: 2010-02-16, 最終更新日: 2024-10-30)

主引用文献

Zhu, Z.,Sun, Z.Y.,Ye, Y.,Voigt, J.,Strickland, C.,Smith, E.M.,Cumming, J.,Wang, L.,Wong, J.,Wang, Y.S.,Wyss, D.F.,Chen, X.,Kuvelkar, R.,Kennedy, M.E.,Favreau, L.,Parker, E.,McKittrick, B.A.,Stamford, A.,Czarniecki, M.,Greenlee, W.,Hunter, J.C.
Discovery of Cyclic Acylguanidines as Highly Potent and Selective beta-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I-Inhibitor Design and Validation
J.Med.Chem., 53:951-965, 2010

PubMed Abstract: A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

PubMed: 20043696
DOI: 10.1021/jm901408p

実験手法

X-RAY DIFFRACTION (1.75 Å)