Inhibitor-Mediated Structural Transition in a Minimal Amyloid Model

Area of Science:

• Biochemistry
• Structural Biology
• Materials Science

Background:

• Amyloid fibril formation is clinically significant but mechanistically unclear.
• Crystallography of minimal amyloid models advanced understanding of fiber architecture and activity.
• The crystal structure of ultimate dipeptide-based amyloids remained unreported.

Purpose of the Study:

• To determine the crystal structure of the minimal amyloid-forming dipeptide Ac-Phe-Phe-NH2 (Ac-FF-NH2).
• To investigate amyloid inhibition using crystallography at the atomic level in a fundamental model.
• To elucidate structural transitions during amyloid inhibition.

Main Methods:

• X-ray crystallography was employed to determine the atomic structure of Ac-FF-NH2.
• Crystallography was used to study the effect of an inhibitor on Ac-FF-NH2 self-assembly.
• Comparative structural analysis of Ac-FF-NH2 in the presence and absence of an inhibitor.

Main Results:

• The crystal structure of Ac-FF-NH2 revealed a canonical β-sheet structure at the atomic level.
• Crystallography enabled the investigation of amyloid inhibition, a novel approach for such small models.
• In the presence of an inhibitor, Ac-FF-NH2 molecules rearranged into a supramolecular 2-fold helix (21 helix).

Conclusions:

• The study provides the atomic-level crystal structure of a fundamental amyloid-forming dipeptide.
• This work establishes a new crystallographic method for studying amyloid inhibition mechanisms.
• The findings offer insights into the structural plasticity of amyloid formation and inhibition processes.