Figure 2: Binding of compound 11 to δ-secretase.
From: Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease
(a) Both active site liganded and free δ-secretase bind to compound 11 which was immobilized on a sam5BLUE biosensor chip. Binding of C189S-prolegumain (red curves), in trans activated C189S-legumain only (dark blue curves) and complexed to cystatin E (light blue curves), δ-secretase (dark green curves) and δ-secretase covalently inhibited with YVAD-chloromethyleketone (δ-secretase+YVAD-cmk, light green curves), was tested at pH 5.0. Cystatin E (grey curves) and papain (black curves) served as a control to test for unspecific binding to the chip. (b) Compound 11 binds to δ-secretase at a site close to the dimer-interaction site in caspases. Active site inhibited δ-secretase was crystallized with compound 11. The active site is labelled with the covalent YVAD-cmk inhibitor and shown in orange sticks, the catalytic Cys189 and His148 in green sticks and compound 11 in blue sticks. (c) Zoom-in view on the compound 11 binding site. (d) Compound 11 binds to the δ-secretase active site. (e) Zoom-in view on the active site. The morpholino group binds into δ-secretase’s S1-pocket. Furthermore, the oxyanion-pocket, formed by Cys189, Gly149 and His148, is also occupied in the structure. The electron density (2Fobs–Fcalc) defining compound 11 is contoured at 1σ over the mean. Interacting residues on δ-secretase are shown as green sticks.
