3D Structure of Ramoplanin: A Potent Inhibitor of Bacterial Cell Wall Synthesis,

Abstract

The 3D structure of ramoplanin was studied by NMR spectroscopy in aqueous solution. A total of 320 interproton distances were determined from a NOESY spectrum and were used as restraints in distance geometry calculations. A structural refinement was carried out by molecular dynamics calculations in a solvent box. The structure of ramoplanin is characterized by two antiparallel β-strands which are formed by the residues 2−7 and 10−14, respectively. The β-strands are connected by six intramolecular hydrogen bonds and a reverse β-turn which is formed by Thr⁸ and Phe⁹ (in positions i+1 and i+2, respectively). Residues 2 and 14 are connected by a loop consisting of Leu¹⁵, Ala¹⁶, Chp¹⁷, and the side chain of Asn². Although residues 14−17 show the formation of a β-turn, only the N-terminal end of the turn is directly connected to one of the β-strands (Gly¹⁴), whereas the C-terminal end (Chp¹⁷) is linked via the side chain of Asn². The 3D conformation of ramoplanin is also stabilized by a hydrophobic cluster of the aromatic sidechains of the residues 3, 9, and 17. This hydrophobic collapse leads to a U-shaped topology of the β-sheet with the β-turn at one end and the loop at the other end. The structure found for ramoplanin differs considerably from the published structure of ramoplanose which might be due to a smaller number of NOE distance restraints used in the previous study.