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Publication Abstract from PubMed

Covalent side-chain cross-links are a versatile method to control peptide folding, particularly when alpha-helical secondary structure is the target. Here, we examine the application of oxime bridges, formed by the chemoselective reaction between aminooxy and aldehyde side chains, for the stabilization of a helical peptide involved in a protein-protein complex. A series of sequence variants of the dimeric coiled coil GCN4-p1 bearing oxime bridges at solvent-exposed positions were prepared and biophysically characterized. Triggered unmasking of a side-chain aldehyde in situ and subsequent cyclization proceed rapidly and cleanly at pH 7 in the folded protein complex. Comparison of folding thermodynamics among a series of different oxime bridges show that the cross links are consistently stabilizing to the coiled coil, with the extent of stabilization sensitive to the exact size and structure of the macrocycle. X-ray crystallographic analysis of a coiled coil with the best cross link in place and a second structure of its linear precursor show how the bridge is accommodated into an alpha-helix. Preparation of a bicyclic oligomer by simultaneous formation of two linkages in situ demonstrates the potential use of triggered oxime formation to both trap and stabilize a particular peptide folded conformation in the bound state.

Oxime Side-Chain Cross-Links in an alpha-Helical Coiled-Coil Protein: Structure, Thermodynamics, and Folding-Templated Synthesis of Bicyclic Species.,Haney CM, Horne WS Chemistry. 2013 Aug 19;19(34):11342-51. doi: 10.1002/chem.201300506. Epub 2013, Jul 10. PMID:23843311^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.