Crystal structure of a fully protected β-O-galactosylated tripeptide

The crystal structure of the fully protected glycotripeptide N-benzyloxycarbonyl-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-l-threonyl-α-aminoisobutyryl-α-aminoisobutyric acid tert-butyl ester [Z-(β-d-GalAc4)-l-Thr-Aib-Aib-OtBu] has been determined by X-ray diffraction. The peptide backbone is fully extended at Thr(1), left-handed helical at Aib(2), while it is right-handed helical at Aib(3). The fully extended conformation at the N-terminal Thr residue is stabilized by an intramolecular H-bond involving the N-1–H and O-1C-1 groups (intramolecularly H-bonded C5 conformation). Two additional intramolecular H-bonds are observed, involving the peptide N–H groups of Aib(2) and Aib(3) as the donors, and the pyranosidic O-5 oxygen atom and the carbonyl oxygen atom of the acetoxy group on C-6 of the sugar, respectively, as the acceptors. Owing to the peptide–sugar H-bonds, the peptide backbone is forced to adopt a conformation dramatically different from the β-bend/310-helical conformation usually observed for Aib-rich peptides. The implications and limitations of these findings on the effect of O-glycosylation on the conformation of natural peptides are briefly outlined.