Structural basis of γ-secretase inhibition and modulation by small molecule drugs

Cell. 2021 Jan 21;184(2):521-533.e14. doi: 10.1016/j.cell.2020.11.049. Epub 2020 Dec 28.


Development of γ-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 γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-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 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β 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 γ-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.

Keywords: cryo-EM; drug; inhibitor; modulator; structure; γ-secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives
  • Alanine / pharmacology
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid Precursor Protein Secretases / ultrastructure
  • Azepines / pharmacology
  • Binding Sites
  • Cryoelectron Microscopy
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Models, Biological
  • Models, Molecular
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology
  • Pharmaceutical Preparations / chemistry*
  • Presenilin-1 / chemistry
  • Presenilin-1 / metabolism
  • Protein Binding / drug effects
  • Protein Conformation
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity / drug effects
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology


  • Azepines
  • BMS 708163
  • Enzyme Inhibitors
  • N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
  • Oxadiazoles
  • Pharmaceutical Preparations
  • Presenilin-1
  • Small Molecule Libraries
  • Sulfonamides
  • Amyloid Precursor Protein Secretases
  • Alanine