The structure of an asymmetric dimer relevant to the mode of action of the glycopeptide antibiotics  Patrick Groves, Mark S Searle, Joel P Mackay, Dudley H Williams  Structure  Volume 2, Issue 8, Pages 747-754 (August 1994) DOI: 10.1016/S0969-2126(94)00075-1

Figure 1 Structure of vancomycin and eremomycin with the hydrogen atom labelling scheme adopted. (a) Shows the region of the structure common to both compounds and (b) shows the distinguishing functional groups. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 1 Structure of vancomycin and eremomycin with the hydrogen atom labelling scheme adopted. (a) Shows the region of the structure common to both compounds and (b) shows the distinguishing functional groups. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 2 Proposed hydrogen-bonding scheme in the eremomycin dimer complex with the cell wall analogue N-acetyl-D-Ala-D-Ala. The backbones of the two antiparallel monomers are shown in bold. Arrows represent hydrogen bonds between the two halves of the dimer, while dotted lines represent hydrogen bonds between the cell wall peptide and the antibiotic. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 3 Schematic views of the two possible eremomycin monomeric structures (a), where the disaccharide units are related by 180° rotations about the bond connecting the glucose sugar to residue 4 (see Figure 1). The two possible symmetric dimer structures are illustrated in (b) and (c), while the single asymmetric dimer is shown in (d); all are obtained from different combinations of the monomer units shown in (a). The disaccharide consists of 4-epi-vancosamine (V) and glucose (G) sugar units. Thus, two sets of signals in the NMR spectrum could be explained either in terms of a mixture of symmetrical dimers in equal proportions or a single asymmetric dimer. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 4 The structures of (a) N-acetyl-D-Ala, (b) pyrrole-2-carboxylate and (c) indole-2-carboxylate. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 5 Portion of the 50ms NOESY spectrum of the eremomycin dimer complex with pyrrole-2-carboxylate (283 K, pH7.0). Each eremomycin monomer has the same atom labels with asterisks distinguishing one eremomycin monomer from the other in the dimer complex. The partial assignment of the epi-vancosamine sugars of the two disaccharides is highlighted, and several intermolecular NOEs identified in boxes (see text for details). NOEs are traced from V5 to both V6 and V7, and subsequently from V7 to V2e and V2a (see Figure 1). Dashed lines trace the correlations for one sugar (V), while solid lines trace the same pattern for its counterpart (V∗). Weak chemical exchange cross-peaks between V6 and V6∗, and V7 and V7∗ are labelled ‘e’. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 6 Conformation of the 4-epi-vancosamine sugar. Hydrogens are labelled V1 to V7. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 7 Restrained energy-minimized structure of the eremomycin dimer complex with pyrrole-2-carboxylate. In (a), the structure of the ligand-bound dimer is viewed along the symmetry axis of the heptapeptide backbone. Chlorine atoms are highlighted as black dots and are in van der Waals contact with atoms of the dimer partner. The overall symmetry of the dimer structure is broken by the disaccharide units that are aligned in a parallel head-to-head arrangement. In (b), the orthogonal σ–π interactions between rings 4 and 6 of one monomer unit and the corresponding rings 6∗ and 4∗, respectively, of its dimer partner are illustrated. Oxygen atoms are shaded. In (c), only the disaccharide units are shown (all atoms) to illustrate the complementarity between the juxtaposed hydrophobic faces that promote dimerization. The epi-vancosamine (V and V∗) and glucose (G and G∗) components of each disaccharide are labelled. The point of attachment of the glucose to ring 4 is marked with ‘x’ the broken line identifies an intermolecular hydrogen bond (2.1å) between G3∗–OH and the ether oxygen of V. Nitrogen atoms are shown in black and oxygen atoms are shaded. In (d), a possible mechanism is illustrated by which ligand binding can cooperatively promote dimerization. The carboxylate anion of a cell wall fragment (shown here for pyrrole-2-carboxylate [–]) forms an amide-mediated salt bridge (bonds black) with the alkylammonium ion [+] of the residue-6 amino sugar in the other half of the dimer. Broken lines identify hydrogen bonds between ligand and antibiotic (left to right: 1.80å, 1.81å, 1.82å, 1.79å), while dotted lines correspond to dimer interface hydrogen bonds (left to right: 1.75å, 2.17å, 1.88å). Only hydrogens involved in hydrogen bonds are illustrated. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 7 Restrained energy-minimized structure of the eremomycin dimer complex with pyrrole-2-carboxylate. In (a), the structure of the ligand-bound dimer is viewed along the symmetry axis of the heptapeptide backbone. Chlorine atoms are highlighted as black dots and are in van der Waals contact with atoms of the dimer partner. The overall symmetry of the dimer structure is broken by the disaccharide units that are aligned in a parallel head-to-head arrangement. In (b), the orthogonal σ–π interactions between rings 4 and 6 of one monomer unit and the corresponding rings 6∗ and 4∗, respectively, of its dimer partner are illustrated. Oxygen atoms are shaded. In (c), only the disaccharide units are shown (all atoms) to illustrate the complementarity between the juxtaposed hydrophobic faces that promote dimerization. The epi-vancosamine (V and V∗) and glucose (G and G∗) components of each disaccharide are labelled. The point of attachment of the glucose to ring 4 is marked with ‘x’ the broken line identifies an intermolecular hydrogen bond (2.1å) between G3∗–OH and the ether oxygen of V. Nitrogen atoms are shown in black and oxygen atoms are shaded. In (d), a possible mechanism is illustrated by which ligand binding can cooperatively promote dimerization. The carboxylate anion of a cell wall fragment (shown here for pyrrole-2-carboxylate [–]) forms an amide-mediated salt bridge (bonds black) with the alkylammonium ion [+] of the residue-6 amino sugar in the other half of the dimer. Broken lines identify hydrogen bonds between ligand and antibiotic (left to right: 1.80å, 1.81å, 1.82å, 1.79å), while dotted lines correspond to dimer interface hydrogen bonds (left to right: 1.75å, 2.17å, 1.88å). Only hydrogens involved in hydrogen bonds are illustrated. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 7 Restrained energy-minimized structure of the eremomycin dimer complex with pyrrole-2-carboxylate. In (a), the structure of the ligand-bound dimer is viewed along the symmetry axis of the heptapeptide backbone. Chlorine atoms are highlighted as black dots and are in van der Waals contact with atoms of the dimer partner. The overall symmetry of the dimer structure is broken by the disaccharide units that are aligned in a parallel head-to-head arrangement. In (b), the orthogonal σ–π interactions between rings 4 and 6 of one monomer unit and the corresponding rings 6∗ and 4∗, respectively, of its dimer partner are illustrated. Oxygen atoms are shaded. In (c), only the disaccharide units are shown (all atoms) to illustrate the complementarity between the juxtaposed hydrophobic faces that promote dimerization. The epi-vancosamine (V and V∗) and glucose (G and G∗) components of each disaccharide are labelled. The point of attachment of the glucose to ring 4 is marked with ‘x’ the broken line identifies an intermolecular hydrogen bond (2.1å) between G3∗–OH and the ether oxygen of V. Nitrogen atoms are shown in black and oxygen atoms are shaded. In (d), a possible mechanism is illustrated by which ligand binding can cooperatively promote dimerization. The carboxylate anion of a cell wall fragment (shown here for pyrrole-2-carboxylate [–]) forms an amide-mediated salt bridge (bonds black) with the alkylammonium ion [+] of the residue-6 amino sugar in the other half of the dimer. Broken lines identify hydrogen bonds between ligand and antibiotic (left to right: 1.80å, 1.81å, 1.82å, 1.79å), while dotted lines correspond to dimer interface hydrogen bonds (left to right: 1.75å, 2.17å, 1.88å). Only hydrogens involved in hydrogen bonds are illustrated. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 7 Restrained energy-minimized structure of the eremomycin dimer complex with pyrrole-2-carboxylate. In (a), the structure of the ligand-bound dimer is viewed along the symmetry axis of the heptapeptide backbone. Chlorine atoms are highlighted as black dots and are in van der Waals contact with atoms of the dimer partner. The overall symmetry of the dimer structure is broken by the disaccharide units that are aligned in a parallel head-to-head arrangement. In (b), the orthogonal σ–π interactions between rings 4 and 6 of one monomer unit and the corresponding rings 6∗ and 4∗, respectively, of its dimer partner are illustrated. Oxygen atoms are shaded. In (c), only the disaccharide units are shown (all atoms) to illustrate the complementarity between the juxtaposed hydrophobic faces that promote dimerization. The epi-vancosamine (V and V∗) and glucose (G and G∗) components of each disaccharide are labelled. The point of attachment of the glucose to ring 4 is marked with ‘x’ the broken line identifies an intermolecular hydrogen bond (2.1å) between G3∗–OH and the ether oxygen of V. Nitrogen atoms are shown in black and oxygen atoms are shaded. In (d), a possible mechanism is illustrated by which ligand binding can cooperatively promote dimerization. The carboxylate anion of a cell wall fragment (shown here for pyrrole-2-carboxylate [–]) forms an amide-mediated salt bridge (bonds black) with the alkylammonium ion [+] of the residue-6 amino sugar in the other half of the dimer. Broken lines identify hydrogen bonds between ligand and antibiotic (left to right: 1.80å, 1.81å, 1.82å, 1.79å), while dotted lines correspond to dimer interface hydrogen bonds (left to right: 1.75å, 2.17å, 1.88å). Only hydrogens involved in hydrogen bonds are illustrated. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)

Figure 8 Structure of teicoplanin. Structure 1994 2, 747-754DOI: (10.1016/S0969-2126(94)00075-1)