3WB4

Crystal Structure of beta secetase in complex with 2-amino-3,6-dimethyl-6-(2-phenylethyl)-3,4,5,6-tetrahydropyrimidin-4-one

3WB4 の概要

• エントリーDOI: 10.2210/pdb3wb4/pdb
• 関連するPDBエントリー: 3WB5
• 分子名称: Beta-secretase 1, GLYCEROL, IODIDE ION, ... (5 entities in total)
• 機能のキーワード: protease 2, asp2, membrane-associated aspartic protease 2, memapsin-2, 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: 1
• 化学式量合計: 47260.55

構造登録者

Yonezawa, S.,Fujiwara, K.,Yamamoto, T.,Hattori, K.,Yamakawa, H.,Muto, C.,Hosono, M.,Tanaka, Y.,Nakano, T.,Takemoto, H.,Arisawa, M.,Shuto, S. (登録日: 2013-05-13, 公開日: 2013-10-02, 最終更新日: 2024-11-20)

主引用文献

Yonezawa, S.,Fujiwara, K.,Yamamoto, T.,Hattori, K.,Yamakawa, H.,Muto, C.,Hosono, M.,Tanaka, Y.,Nakano, T.,Takemoto, H.,Arisawa, M.,Shuto, S.
Conformational restriction approach to beta-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations
Bioorg.Med.Chem., 21:6506-6522, 2013

PubMed Abstract: For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.

PubMed: 24051074
DOI: 10.1016/j.bmc.2013.08.036

実験手法

X-RAY DIFFRACTION (2.25 Å)