5HOX

X-ray crystallographic structure of an A-beta 17_36 beta-hairpin. Synchrotron data set. (LVFFAEDCGSNKCAII(SAR)LMV).

Summary for 5HOX

• Entry DOI: 10.2210/pdb5hox/pdb
• Related: 5HOW 5HOY
• Descriptor: Amyloid beta A4 protein, O-(O-(2-AMINOPROPYL)-O'-(2-METHOXYETHYL)POLYPROPYLENE GLYCOL 500) (3 entities in total)
• Functional Keywords: amyloid, oligomer, beta-hairpin, alzheimer's, protein fibril, de novo protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 14156.20

Authors

Kreutzer, A.G.,Nowick, J.S.,Spencer, R.K. (deposition date: 2016-01-19, release date: 2016-03-23, Last modification date: 2023-09-27)

Primary citation

Kreutzer, A.G.,Hamza, I.L.,Spencer, R.K.,Nowick, J.S.
X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an A beta 17-36 beta-Hairpin.
J.Am.Chem.Soc., 138:4634-4642, 2016

PubMed Abstract: High-resolution structures of oligomers formed by the β-amyloid peptide Aβ are needed to understand the molecular basis of Alzheimer's disease and develop therapies. This paper presents the X-ray crystallographic structures of oligomers formed by a 20-residue peptide segment derived from Aβ. The development of a peptide in which Aβ17-36 is stabilized as a β-hairpin is described, and the X-ray crystallographic structures of oligomers it forms are reported. Two covalent constraints act in tandem to stabilize the Aβ17-36 peptide in a hairpin conformation: a δ-linked ornithine turn connecting positions 17 and 36 to create a macrocycle and an intramolecular disulfide linkage between positions 24 and 29. An N-methyl group at position 33 blocks uncontrolled aggregation. The peptide readily crystallizes as a folded β-hairpin, which assembles hierarchically in the crystal lattice. Three β-hairpin monomers assemble to form a triangular trimer, four trimers assemble in a tetrahedral arrangement to form a dodecamer, and five dodecamers pack together to form an annular pore. This hierarchical assembly provides a model, in which full-length Aβ transitions from an unfolded monomer to a folded β-hairpin, which assembles to form oligomers that further pack to form an annular pore. This model may provide a better understanding of the molecular basis of Alzheimer's disease at atomic resolution.

PubMed: 26967810
DOI: 10.1021/jacs.6b01332

Experimental method

X-RAY DIFFRACTION (1.9 Å)