NMR study of mersacidin and lipid II interaction in dodecylphosphocholine micelles. Conformational changes are a key to antimicrobial activity.
Mersacidin belongs to the type B lantibiotics (lanthionine-containing antibiotics) that contain post-translationally modified amino acids and cyclic ring structures. It targets the cell wall precursor lipid II and thereby inhibits cell wall synthesis. In light of the emerging antibiotics resistance problem, the understanding of the antibacterial activity on a structural basis provides a key to circumvent this issue. Here we present solution NMR studies of mersacidin-lipid II interaction in dodecylphosphocholine (DPC) micelles. Distinct solution structures of mersacidin were determined in three different states: in water/methanol solution and in DPC micelles with and without lipid II. The structures in various sample conditions reveal remarkable conformational changes in which the junction between Ala-12 and Abu-13 (where Abu is aminobutyric acid) effectively serves as the hinge for the opening and closure of the ring structures. The DPC micelle-bound form resembles the previously determined NMR and x-ray crystal structures of mersacidin in pure methanol but substantially deviates from the other two states in our current report. The structural changes delineate the large chemical shift perturbations observed during the course of a two-step (15)N-(1)H heteronuclear single quantum coherence titration. They also modulate the surface charge distribution of mersacidin suggesting that electrostatics play a central role in the mersacidin-lipid II interaction. The observed conformational adaptability of mersacidin might be a general feature of lipid II-interacting antibiotics/peptides.
Hsu
Shang-Te D
ST
NMR Department, Bijvoet Center for Biomolecular Research, Utrecht University, 3584CH, Utrecht, The Netherlands.
Breukink
Eefjan
E
Bierbaum
Gabriele
G
Sahl
Hans-Georg
HG
de Kruijff
Ben
B
Kaptein
Rob
R
van Nuland
Nico A J
NA
Bonvin
Alexandre M J J
AM
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification; D001407:Bacillus / Q000737:chemistry; D001430:Bacteriocins; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides; D010456:Peptides, Cyclic / Q000737:chemistry*; D010767:Phosphorylcholine / Q000031:analogs & derivatives*; D011487:Protein Conformation; D012996:Solutions; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D008823:Micelles; D010455:Peptides; D010456:Peptides, Cyclic; D012996:Solutions; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D010767:Phosphorylcholine; C069959:mersacidin; C028810:dodecylphosphocholine