Structure of the Protease Domain of Memapsin 2 (
-Secretase) Complexed with Inhibitor
Lin Hong,1
Gerald Koelsch,1
Xinli Lin,1
Shili Wu,1
Simon Terzyan,2
Arun K. Ghosh,3
Xuenjun C. Zhang,2
Jordan Tang14*
Memapsin 2 (
-secretase) is a membrane-associated
aspartic protease involved in the production of -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.
1 Protein Studies Program and
2 Crystallography Program, Oklahoma Medical Research
Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
3 Department of Chemistry, University of Illinois at
Chicago, Chicago, IL 60607, USA.
4 Department of
Biochemistry and Molecular Biology, University of Oklahoma Health
Sciences Center, Oklahoma City, OK 73104, USA.
*
To whom correspondence should be addressed. E-mail:
jordan-tang{at}omrf.ouhsc.edu
