| First Author | Ohki Y | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 23 | Pages | 4815-24 |
| PubMed ID | 22002539 | Mgi Jnum | J:180062 |
| Mgi Id | MGI:5305360 | Doi | 10.1038/emboj.2011.372 |
| Citation | Ohki Y, et al. (2011) Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J 30(23):4815-24 |
| abstractText | Amyloid-beta peptide ending at the 42nd residue (Abeta42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Abeta42 production are termed gamma-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the gamma-secretase, thereby decreasing production of Abeta42, possibly by enhancing its conversion to Abeta38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs. |
