5F1T: Crystal structure of a macrocyclic peptide containing fragments from alpha-synuclein 36-55

Oligomeric assemblies of the protein alpha-synuclein are thought to cause neurodegeneration in Parkinson's disease and related synucleinopathies. Characterization of alpha-synuclein oligomers at high resolution is an outstanding challenge in the field of structural biology. The absence of high-resolution structures of oligomers formed by alpha-synuclein impedes understanding the synucleinopathies at the molecular level. This paper reports the X-ray crystallographic structure of oligomers formed by a peptide derived from residues 36-55 of alpha-synuclein. The peptide 1a adopts a beta-hairpin structure, which assembles in a hierarchical fashion. Three beta-hairpins assemble to form a triangular trimer. Three copies of the triangular trimer assemble to form a basket-shaped nonamer. Two nonamers pack to form an octadecamer. Molecular modeling suggests that full-length alpha-synuclein may also be able to assemble in this fashion. Circular dichroism spectroscopy demonstrates that peptide 1a interacts with anionic lipid bilayer membranes, like oligomers of full-length alpha-synuclein. LDH and MTT assays demonstrate that peptide 1a is toxic toward SH-SY5Y cells. Comparison of peptide 1a to homologues suggests that this toxicity results from nonspecific interactions with the cell membrane. The oligomers formed by peptide 1a are fundamentally different than the proposed models of the fibrils formed by alpha-synuclein and suggest that alpha-Syn36-55, rather than the NAC, may nucleate oligomer formation.
PDB ID: 5F1TDownload
MMDB ID: 137503
PDB Deposition Date: 2015/11/30
Updated in MMDB: 2018/06
Experimental Method:
x-ray diffraction
Resolution: 1.971  Å
Source Organism:
Similar Structures:
Biological Unit for 5F1T: octadecameric; determined by author and by software (PISA)
Molecular Components in 5F1T
Label Count Molecule
Proteins (18 molecules)
Macrocyclic Peptide
Molecule annotation
Chemicals (16 molecules)
* Click molecule labels to explore molecular sequence information.

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