ASYMMETRY IN THE STRUCTURE OF GLYCOPEPTIDE ANTIBIOTIC DIMERS - NMR STUDIES OF THE RISTOCETIN A COMPLEX WITH A BACTERIAL CELL WALL ANALOGUE

摘要

The solution structure of a dimer complex of the glycopeptide antibiotic ristocetin A has been determined from NOE constraints, energy minimization, and molecular dynamics calculations. The structure is that of an asymmetric dimer in which the conformation of the two monomeric units differs in the orientation of the tetrasaccharide attached to the aromatic ring of residue 4. Although hydrogen bonding interactions between the peptide backbones of the two antibiotic monomers occur in a symmetrical head-to-tail orientation, the overall dimer assymmetry arises as a consequence of a parallel, head-to-head alignment of the tetrasaccharides. Thus, in the two monomeric antibiotic conformations that constitute the dimer, the orientations of the tetrasaccharides are related by an approximate to 180 degrees rotation about the glucose-ring 4 glycosidic bond. The quite different orientation of the tetrasaccharide in each half of the dimer results in significant differences in binding interactions with cell wall peptides occupying the two different sites on the dimer. In one site, the hydrophobic face of glucose interacts with the methyl group of the C-terminal D-alanine of cell wall analogues, while the rhamnose sugar of the same tetrasachharide may act as a hydrophilic ''cap'' where three hydroxyl groups on the edge of the sugar can mimic a group of water molecules through a network of hydrogen bonds. An arabinose sugar of the other tetrasaccharide occupies a similar position to the rhamnose in the second ligand binding site; its single hydroxyl group may be less effective as a hydrophilic cap, and the hydrophobic interaction to a glucose face (see above) cannot now take place. These observations lead to the conclusion that there may be a marked difference in the ligand binding affinities for the two sites. This conclusion has been confirmed experimentally. [References: 26]