The amyloidosis family of diseases is characterized by the deposition of soluble protein into insoluble polymeric fibrils (amyloid) with concomitant tissue damage and interruption of normal cellular physiology. The pathology of amyloid diseases may be prevented or reversed by disrupting the interactions that stabilize amyloid or binding of amyloid to cellular proteins. However, the design of such medicinal compounds is difficult since the structure of the amyloid monomers and the specific interactions that stabilize amyloid are unknown. Low resolution spectroscopic and biochemical data have been incorporated into a preliminary model of amyloid. Solid State NMR (ssNMR) dipolar recoupling techniques will be used to obtain the local and global structure of the amyloid sub-units. These constraints will be built into an existing model of amyloid structure and analyzed in the context of the biochemical characterization of amyloid structure and toxicity. Particular intention will be directed to amino acid residues which interact with cellular proteins as understanding these interactions may facilitate the design of pharmaceutical agents.
|Astrof, Nathan S; Griffin, Robert G (2002) Soft-triple resonance solid-state NMR experiments for assignments of U-13C, 15N labeled peptides and proteins. J Magn Reson 158:157-63|
|Jaroniec, Christopher P; MacPhee, Cait E; Astrof, Nathan S et al. (2002) Molecular conformation of a peptide fragment of transthyretin in an amyloid fibril. Proc Natl Acad Sci U S A 99:16748-53|
|Astrof, N S; Lyon, C E; Griffin, R G (2001) Triple resonance solid state NMR experiments with reduced dimensionality evolution periods. J Magn Reson 152:303-7|
|Rosay, M; Zeri, A C; Astrof, N S et al. (2001) Sensitivity-enhanced NMR of biological solids: dynamic nuclear polarization of Y21M fd bacteriophage and purple membrane. J Am Chem Soc 123:1010-1|