Uncovering the Binding Mode of γ-Secretase Inhibitors

Abstract

Knowledge of how transition state inhibitors bind to γ-secretase is of major importance for the design of new Alzheimer's disease therapies. Based on the known structure of γsecretase in complex with a fragment of the amyloid precursor protein we have generated a structural model of γ-secretase in complex with the effective L-685,458 transition state inhibitor. The predicted binding mode is in excellent agreement with experimental data, mimicking all enzyme-substrate interactions at the active site and forming the relevant transition state geometry with the active site aspartate residues. In addition, we found that the stability of the complex is very likely also sensitive to the pH value. Comparative simulations on the binding of L-685,458 and the epimer L682,679 allowed us to explain the strongly reduced affinity of the epimer for γ-secretase. The structural model could form a valuable basis for the design of new or modified γ-secretase inhibitors.

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

“…Relying on the atomic coordinates of g-secretase bound to substrate (Yang et al, 2019;Zhou et al, 2019), the binding mode of L458 by PS1 was correctly predicted by a molecular dynamics simulation (Hitzenberger and Zacharias, 2019). Structural comparison reveals an RMSD of 1.60 A ˚over 296 aligned Ca atoms between the simulated PS1 and our structurally observed PS1, with some notable changes at the inhibitor binding pocket and the loop-1 region (Figure S4C).…”

Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface

“…The wide variety of diffusion coefficients in tracks could reflect different conformational states of γ-secretase, as shown previously for other proteins ( Suzuki et al, 2012 ; Constals et al, 2015 ). Recent progress in understanding the structural biology of PSEN1/γ-secretase showed the existence of compact/semi-open conformations likely reflecting the active state of the enzyme versus the rigidifying effects of GSI ( Bai et al, 2015a ; Bai et al, 2015b ; Aguayo-Ortiz and Dominguez, 2018 ; Hitzenberger and Zacharias, 2019 ; Zhou et al, 2019 ). To test if conformational changes affected PSEN1/γ-secretase diffusion at the PM, we treated mEOS3.2-PSEN1 MEFs with the GSIs DAPT and L-685,458 (InhX).…”

“…To test if conformational changes affected PSEN1/γ-secretase diffusion at the PM, we treated mEOS3.2-PSEN1 MEFs with the GSIs DAPT and L-685,458 (InhX). DAPT ‘locks’ the γ-secretase structure in an intermediate state between the active and inactive conformation, while InhX is a transition-state analog that binds to the active site in a similar manner as the substrate APP ( Hitzenberger and Zacharias, 2019 ), inducing a ‘compact/semi-open’ conformation ( Elad et al, 2015 ). Exposure to GSI did not affect the MSD, diffusion coefficient or the overall distribution of Log 10 D ( Figure 3A–E ).…”

Characterizing the Chemical Space of γ-Secretase Inhibitors and Modulators

“…These compounds recognize different binding sites in PS and modulate the cleavage of APP by decreasing the formation of amyloidogenic Aβ42 peptides and promoting the production of shorter Aβ isoforms, without affecting the cleavage of other substrates such as Notch. 9,12,13,17 Although the GS inhibition by transition state inhibitors (TSI) is relative clear, 18,19 the mechanisms of inhibition and modulation of GS by other compounds remain unknown. Computational approaches such as molecular dynamics (MD) simulations have been crucial to analyze GS dynamic behavior and its conformational ensemble.…”