title: Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1.
abstract: Amyloid-β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the γ-secretase, thereby decreasing production of Aβ42, possibly by enhancing its conversion to Aβ38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs.
authors: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Yu
authors: Y
authors: Ohki
authors: Takuya
authors: T
authors: Higo
authors: Kengo
authors: K
authors: Uemura
authors: Naoaki
authors: N
authors: Shimada
authors: Satoko
authors: S
authors: Osawa
authors: Oksana
authors: O
authors: Berezovska
authors: Satoshi
authors: S
authors: Yokoshima
authors: Tohru
authors: T
authors: Fukuyama
authors: Taisuke
authors: T
authors: Tomita
authors: Takeshi
authors: T
authors: Iwatsubo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000544:Alzheimer Disease / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D053764:Presenilin-1 / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D010880:Piperidines; D053764:Presenilin-1; C078639:amyloid beta-protein (1-38); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases