Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560

Inhibition of gamma-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of gamma-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing gamma-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 angstrom. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting gamma-secretase. Presenilin isoforms (PS1 and PS2) containing gamma-secretase show contrasting sensitivity to MRK-560. Here, the authors determined cryo-EM structures of PS1/PS2-complexes treated with MRK-560 and identified key residues responsible for the isoform-dependent selectivity.

Automated summary

The study reveals the isoform-dependent sensitivity of gamma-secretase containing Presenilin isoforms (PS1 and PS2) to the inhibitor MRK-560. Cryo-EM structures of PS1/PS2 complexes treated with MRK-560 were determined, and key residues responsible for the isoform-dependent selectivity were identified.