Crystal Structure of Memapsin 2 (β-Secretase) in Complex with an Inhibitor OM00-3

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Abstract
The structure of the catalytic domain of human memapsin 2 bound to an inhibitor OM00-3 (Glu-Leu-Asp-Leu*Ala-Val-Glu-Phe, Ki = 0.3 nM, the asterisk denotes the hydroxyethylene transition-state isostere) has been determined at 2.1 Å resolution. Uniquely defined in the structure are the locations of S3‘ and S4‘ subsites, which were not identified in the previous structure of memapsin 2 in complex with the inhibitor OM99-2 (Glu-Val-Asn-Leu*Ala-Ala-Glu-Phe, Ki = 1 nM). Different binding modes for the P2 and P4 side chains are also observed. These new structural elements are useful for the design of new inhibitors. The structural and kinetic data indicate that the replacement of the P2‘ alanine in OM99-2 with a valine in OM00-3 stabilizes the binding of P3‘ and P4‘.