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Structure paper

TitleMolecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 6299, Year 2022
Publish dateOct 22, 2022
AuthorsXuefei Guo / Yumeng Wang / Jiayao Zhou / Chen Jin / Jiaoni Wang / Bojun Jia / Dan Jing / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi /
PubMed AbstractInhibition 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 linksNat Commun / PubMed:36272978 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.4 Å
Structure data

33624

7y5t

EMDB-33624, PDB-7y5t:
CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560
Method: EM (single particle) / Resolution: 2.9 Å

33628

7y5x

EMDB-33628, PDB-7y5x:
CryoEM structure of PS2-containing gamma-secretase treated with MRK-560
Method: EM (single particle) / Resolution: 3.0 Å

33629

7y5z

EMDB-33629, PDB-7y5z:
CryoEM structure of human PS2-containing gamma-secretase
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

ChemComp-IGD:
~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/HYDROLASE / Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex / presenilin / presenilin-2

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