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Title | Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. |
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Journal, issue, pages | Nat Commun, Vol. 13, Issue 1, Page 6299, Year 2022 |
Publish date | Oct 22, 2022 |
Authors | Xuefei Guo / Yumeng Wang / Jiayao Zhou / Chen Jin / Jiaoni Wang / Bojun Jia / Dan Jing / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi / |
PubMed Abstract | Inhibition of γ-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, ...Inhibition of γ-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 γ-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing γ-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 Å. 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 γ-secretase. |
External links | Nat Commun / PubMed:36272978 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.9 - 3.4 Å |
Structure data | EMDB-33624, PDB-7y5t: EMDB-33628, PDB-7y5x: EMDB-33629, PDB-7y5z: |
Chemicals | ChemComp-NAG: ChemComp-PC1: ChemComp-IGD: ChemComp-CLR: |
Source |
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Keywords | MEMBRANE PROTEIN/HYDROLASE / Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex / presenilin / presenilin-2 |