期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 136, 期 36, 页码 12682-12690出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja505713y
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资金
- National Institutes of Health [5R01GM097562]
- Vertex Pharmaceuticals
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
A macrocyclic beta-sheet peptide containing two nonapeptide segments based on A beta(1523) (QKLVFFAED) forms fibril-like assemblies of oligomers in the solid state. The X-ray crystallographic structure of macrocyclic beta-sheet peptide 3 was determined at 1.75 angstrom resolution. The macrocycle forms hydrogen-bonded dimers, which further assemble along the fibril axis in a fashion resembling a herringbone pattern. The extended beta-sheet comprising the dimers is laminated against a second layer of dimers through hydrophobic interactions to form a fibril-like assembly that runs the length of the crystal lattice. The second layer is offset by one monomer subunit, so that the fibril-like assembly is composed of partially overlapping dimers, rather than discrete tetramers. In aqueous solution, macrocyclic beta-sheet 3 and homologues 4 and 5 form discrete tetramers, rather than extended fibril-like assemblies. The fibril-like assemblies of oligomers formed in the solid state by macrocyclic beta-sheet 3 represent a new mode of supramolecular assembly not previously observed for the amyloidogenic central region of A beta. The structures observed at atomic resolution for this peptide model system may offer insights into the structures of oligomers and oligomer assemblies formed by full-length A beta and may provide a window into the propagation and replication of amyloid oligomers.
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