9bi3
Crystal structure of macrocycle containing Abeta17-23 (LVF(a-Me-F)AED) and Abeta30-36 (AIIGL(ORN)V)Crystal structure of macrocycle containing Abeta17-23 (LVF(a-Me-F)AED) and Abeta30-36 (AIIGL(ORN)V)
Structural highlights
Publication Abstract from PubMedThe assembly of the beta-amyloid peptide Abeta into toxic oligomers plays a significant role in the neurodegeneration associated with the pathogenesis of Alzheimer's disease. Our laboratory has developed N-methylation as a tool to enable X-ray crystallographic studies of oligomers formed by macrocyclic beta-hairpin peptides derived from Abeta. In this investigation, we set out to determine whether alpha-methylation could be used as an alternative to N-methylation in studying the oligomerization of a beta-hairpin peptide derived from Abeta. alpha-Methylation permits the crystallographic assembly of a triangular trimer and ball-shaped dodecamer, resembling assemblies formed by the N-methylated homolog. Subtle differences are observed in the conformation of the alpha-methylated peptide when compared to the N-methylated homolog. Notably, alpha-methylation appears to promote a flatter and more extended beta-sheet conformation than that of N-methylated beta-sheets or a typical unmodified beta-sheet. alpha-Methylation provides an alternative to N-methylation in X-ray crystallographic studies of oligomers formed by peptides derived from Abeta, with the attractive feature of preserving NH hydrogen-bond donors along the peptide backbone. alpha-Methylation Enables the X-ray Crystallographic Observation of Oligomeric Assemblies Formed by a beta-Hairpin Peptide Derived from Abeta.,Samdin TD, Kreutzer AG, Sahrai V, Wierzbicki M, Nowick JS J Org Chem. 2025 Jan 10;90(1):394-400. doi: 10.1021/acs.joc.4c02344. Epub 2024 , Dec 17. PMID:39689228[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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