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. Author manuscript; available in PMC: 2017 May 18.
Published in final edited form as: ACS Chem Biol. 2015 Jun 10;10(8):1925–1931. doi: 10.1021/acschembio.5b00321

Figure 5.

Figure 5

Model for the change in active site conformation of γ-secretase and SPP that occurs upon binding by GSIs and GSMs. We propose that the GSIs and GSMs studied here allosterically bind to γ-secretase and SPP, causing a conformational change in the active sites of the enzymes. Surprisingly, the induced conformational change is opposite for the two enzymes, as evidenced by their binding to active site-directed probes. Specifically, GSIs cause decreased binding between γ-secretase and probe while increasing binding between SPP and probe. GSMs cause little change in binding between γ-secretase and probe but reduce binding between SPP and probe. This suggests a model in which GSIs cause the active site of γ-secretase to assume a “closed” conformation but have the reverse impact on the active site structure of SPP.