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

Hong, Lin
Koelsch, Gerald
Lin, Xinli
Wu, Shili
Terzyan, Simon
Ghosh, Arun K.
Zhang, Xuenjun C.
Tang, Jordan

¹Protein Studies Program and ²Crystallography Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA. ³Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA. ⁴Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

*To whom correspondence should be addressed. E-mail: [email protected]

24 May 2000; accepted 17 August 2000

Science 290(5489):p 150-153, October 6, 2000.

Memapsin 2 (β-secretase) is a membrane-associated aspartic protease involved in the production of β-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.