7y5z

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CryoEM structure of human PS2-containing gamma-secretase

Structural highlights

7y5z is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.4Å
Ligands:BMA, CLR, NAG, PC1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NICA_HUMAN Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry.

Function

NICA_HUMAN Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex.

Publication Abstract from PubMed

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 A. 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.

Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.,Guo X, Wang Y, Zhou J, Jin C, Wang J, Jia B, Jing D, Yan C, Lei J, Zhou R, Shi Y Nat Commun. 2022 Oct 22;13(1):6299. doi: 10.1038/s41467-022-33817-5. PMID:36272978[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
1 reviews cite this structure
New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.
De et al. (2024)
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4 other articles
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See Also

References

  1. ↑ 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. 2022 Oct 22;13(1):6299. doi: 10.1038/s41467-022-33817-5. PMID:36272978 doi:http://dx.doi.org/10.1038/s41467-022-33817-5

Contents


PDB ID 7y5z

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OCA

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