6lr4

Publication Abstract from PubMed

Development of gamma-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target gamma-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human gamma-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 A. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the beta strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of gamma-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors.

Structural basis of gamma-secretase inhibition and modulation by small molecule drugs.,Yang G, Zhou R, Guo X, Yan C, Lei J, Shi Y Cell. 2021 Jan 21;184(2):521-533.e14. doi: 10.1016/j.cell.2020.11.049. Epub 2020 , Dec 28. PMID:33373587^[1]

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