2009
DOI: 10.1073/pnas.0910757106
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Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Abstract: ␥-Secretase cleaves multiple substrates within the transmembrane domain that include the amyloid precursor protein as well as the Notch family of receptors. These substrates are associated with Alzheimer disease and cancer. Despite extensive investigation of this protease, little is known regarding the regulation of ␥-secretase specificity. To discover selective inhibitors for drug development and for probing the mechanisms of ␥-secretase specificity, we screened chemical libraries and consequently developed a… Show more

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Cited by 75 publications
(81 citation statements)
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“…Furthermore, L458 and compound E inhibited ␥-secretase activity with IC 50 values of 0.7 nM and 1 nM in our assay, respectively (Fig. 2E), and these values are similar to the reported IC 50 values of A␤40 inhibition (25,32,35). In addition, we determined that ␥-secretase cleaved N1-Sb1 with an apparent K m value of 0.15 Ϯ 0.03 M (Fig.…”
Section: Ps1 Mutationssupporting
confidence: 89%
See 2 more Smart Citations
“…Furthermore, L458 and compound E inhibited ␥-secretase activity with IC 50 values of 0.7 nM and 1 nM in our assay, respectively (Fig. 2E), and these values are similar to the reported IC 50 values of A␤40 inhibition (25,32,35). In addition, we determined that ␥-secretase cleaved N1-Sb1 with an apparent K m value of 0.15 Ϯ 0.03 M (Fig.…”
Section: Ps1 Mutationssupporting
confidence: 89%
“…L-685,458 (L458), an aspartyl protease transition state mimic that interacts with the active site of ␥-secretase (Fig. 1A), has been a valuable tool to study ␥-secretase (15,25). Therefore, we have generated various potent photoactivatable probes through "photophore walking," in which the photoactivatable benzophenone is separately incorporated into different positions along the peptidomimetic core structure of L458.…”
Section: Ps1 Mutationsmentioning
confidence: 99%
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“…We then examined the accessibility of PS1ΔE9 and PS1ΔE9-D385A to an active-site directed probe JC-8, which has been shown to label active γ-secretase (25)(26)(27). We show that photoactivated JC-8 labels PS1ΔE9 in proteoliposomes (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The procedure similar to that described earlier (18,26,27) was used to photo-crosslink JC-8 and targets in proteoliposomes. Fresh proteoliposomes (600 μl) containing various PS1 variants in the presence of 0.25% CHAPSO were preincubated with or without L458 (1 μM) at 37°C for 30 min.…”
Section: Methodsmentioning
confidence: 99%