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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS010964-01
Application #
6056667
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Murphy, Diane
Project Start
2000-01-01
Project End
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Organized Research Units
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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