Structure of the Protease Domain of Memapsin 2 (β-Secretase) Complexed with Inhibitor

作者：Hong Lin, Gerald Koelsch, Xinli Lin, Shili Wu, Simon S. Terzyan, Arun Kumar Ghosh, Xuenjun C. Zhang, Jordan Tang · 发表于：Science · 年份：2000 · DOI：10.1126/science.290.5489.150 · 被引用次数：713 · 研究领域：Alzheimer's disease research and treatments、Computational Drug Discovery Methods、Protein Structure and Dynamics

Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-amyloid peptide in Alzheimer's disease and is a major target for drug design. We determined the crystal structure of the protease domain of human memapsin 2 complexed to an eight-residue inhibitor at 1.9 angstrom resolution. The active site of memapsin 2 is more open and less hydrophobic than that of other human aspartic proteases. The subsite locations from S4 to S2' are well defined. A kink of the inhibitor chain at P2' and the change of chain direction of P3' and P4' may be mimicked to provide inhibitor selectivity.