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Nonspecificity of Binding of γ-Secretase Modulators to the Amyloid Precursor Protein

2009; American Chemical Society; Volume: 48; Issue: 50 Linguagem: Inglês

10.1021/bi901839d

1943-295X

Andrew J. Beel, Paul J. Barrett, Paul D. Schnier, Stephen A. Hitchcock, Dhanashri Bagal, Charles R. Sanders, John B. Jordan,

Drug Transport and Resistance Mechanisms

Evidence that certain gamma-secretase modulators (GSMs) target the 99-residue C-terminal domain (C99) of the amyloid precursor protein, a substrate of gamma-secretase, but not the protease complex itself has been presented [Kukar, T. L., et al. (2008) Nature 453, 925-929]. Here, NMR results demonstrate a lack of specific binding of these GSMs to monodisperse C99 in LMPG micelles. In addition, results indicate that C99 was likely to have been aggregated in some of the key experiments of the previous work and that binding of GSMs to these C99 aggregates is also of a nonspecific nature.