. Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10544-9. Epub 2014 Jul 9 PubMed.

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  1. This study of the Tomita and Iwatsubo laboratories is exciting. It provides via a whole series of cleverly designed and carefully executed experiments a first glimpse into the mechanism of the γ-secretase modulators (GSM). The paper identifies several critical residues in transmembrane domains 2 and 5 and hydrophilic loop 1 that are important for the GSM binding, defining an extracellular site that allosterically affects the catalytic site of γ-secretase in the cell membrane. The paper also provides evidence that the APH1 subunits contribute to the allosteric pocket, something also suggested before by us based on completely different approaches (Acx et al., 2014Serneels et al., 2009). The recent structure of γ-secretase (Lu et al., 2014) provides a new, stimulating framework for these type of approaches. This and much more work along these lines will ultimately provide the level of structure–function insights needed to develop better and more safe drugs that target γ-secretases. It's news we need so much after the overt and exaggerated pessimism that pervaded the field following the failed semagacestat and avagacestat clinical trials.

    References:

    . Signature amyloid β profiles are produced by different γ-secretase complexes. J Biol Chem. 2014 Feb 14;289(7):4346-55. Epub 2013 Dec 13 PubMed.

    . gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science. 2009 May 1;324(5927):639-42. Epub 2009 Mar 19 PubMed.

    . Three-dimensional structure of human γ-secretase. Nature (2014) doi:10.1038/nature13567

    View all comments by Lucia Chavez-Gutierrez

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  1. Scientists Pinpoint γ-Secretase Modulator Binding Spot