1XN3

Crystal structure of Beta-secretase bound to a long inhibitor with additional upstream residues.

1XN3 の概要

• エントリーDOI: 10.2210/pdb1xn3/pdb
• 関連するPDBエントリー: 1FKN 1M4H 1SGZ 1XN2
• 分子名称: Beta-secretase 1, Peptidic inhibitor (3 entities in total)
• 機能のキーワード: bace, alzheimer's disease, 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: 5
• 化学式量合計: 174904.04

構造登録者

Turner III, R.T.,Hong, L.,Koelsch, G.,Ghosh, A.K.,Tang, J. (登録日: 2004-10-04, 公開日: 2005-03-22, 最終更新日: 2024-10-30)

主引用文献

Turner III, R.T.,Hong, L.,Koelsch, G.,Ghosh, A.K.,Tang, J.
Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase).
Biochemistry, 44:105-112, 2005

PubMed Abstract: Memapsin 2 (beta-secretase) is the membrane-anchored aspartic protease that initiates the cleavage of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta (Abeta), a major factor in the pathogenesis of Alzheimer's disease. The active site of memapsin 2 has been shown, with kinetic data and crystal structures, to bind to eight substrate residues (P(4)-P(4)'). We describe here that the addition of three substrate residues from P(7) to P(5) strongly influences the hydrolytic activity by memapsin 2 and these subsites prefer hydrophobic residues, especially tryptophan. A crystal structure of memapsin 2 complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the binding positions of P(5)-P(7) residues. Kinetic studies revealed that the addition of these substrate residues contributes to the decrease in K(m) and increase in k(cat) values, suggesting that these residues contribute to both substrate recognition and transition-state binding. The crystal structure of a new inhibitor, OM03-4 (K(i) = 0.03 nM), bound to memapsin 2 revealed the interaction of a tryptophan with the S(6) subsite of the protease.

PubMed: 15628850
DOI: 10.1021/bi048106k

実験手法

X-RAY DIFFRACTION (2 Å)