Gertsik N, Am Ende CW, Geoghegan KF, Nguyen C, Mukherjee P, Mente S, Seneviratne U, Johnson DS, Li YM. Mapping the Binding Site of BMS-708163 on γ-Secretase with Cleavable Photoprobes. Cell Chem Biol. 2017 Jan 19;24(1):3-8. Epub 2017 Jan 5 PubMed.
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K.U.Leuven and V.I.B.
High-resolution structures of γ-secretase have revealed the architecture of one of the most intriguing proteases. Moreover, co-structures with the allosteric inhibitor DAPT and a short co-purifying peptide uncovered the pocket and interaction mode for DAPT and possibly the substrate binding site in presenilin. But most importantly, the elucidation of the γ-secretase structure opened a new era for experimentalists working on the protease complex family.
In this paper, Li, Johnson, and colleagues present a beautiful exercise in which elegant experimental approaches, assisted with theoretical structural predictions, provide complementary insights into how avagacestat, an inhibitor tested in clinical trials a few years ago, binds and functionally silences γ-secretase. The authors tested alternative chemistries to label and identify the residues in γ-secretase that are involved in the binding of avagacestat. The experimental information guided theoretical docking studies of the inhibitor in the high-resolution structure and provided a model for its interaction with the catalytic presenilin subunit. Intriguingly, the binding sites of the allosteric DAPT and avagacestat inhibitors partially overlap.
Available models for different presenilin-inhibitor interactions offer the opportunity to investigate, in depth, the molecular bases of γ-secretase inhibition. The outcome may have significance for the development of “selective” probes that target the processing of particular substrates, or specific types of proteases complexes. Of relevance, similar exercises using allosteric modulators may reveal the bases of allosterism in γ-secretases and add motion and functional significance to the current static views of the protease.
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