7Y5T

CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560

Summary for 7Y5T

• Entry DOI: 10.2210/pdb7y5t/pdb
• EMDB information: 33624
• Descriptor: Nicastrin, CHOLESTEROL, Presenilin-1, ... (10 entities in total)
• Functional Keywords: intramembrane protease, gamma-secretase, presenilin-1, membrane protein, membrane protein-hydrolase complex, membrane protein/hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 179871.32

Authors

Guo, X.,Wang, Y.,Zhou, J.,Jin, C.,Wang, J.,Jia, B.,Jing, D.,Yan, C.,Lei, J.,Zhou, R.,Shi, Y. (deposition date: 2022-06-17, release date: 2022-11-02, Last modification date: 2024-10-30)

Primary citation

Guo, X.,Wang, Y.,Zhou, J.,Jin, C.,Wang, J.,Jia, B.,Jing, D.,Yan, C.,Lei, J.,Zhou, R.,Shi, Y.
Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
Nat Commun, 13:6299-6299, 2022

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, 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.

PubMed: 36272978
DOI: 10.1038/s41467-022-33817-5

Experimental method

ELECTRON MICROSCOPY (2.9 Å)