Vancomycin forms ligand-mediated supramolecular complexes.
The emergence of resistance to vancomycin and related glycopeptide antibiotics is spurring efforts to develop new antimicrobial therapeutics. High-resolution structural information about antibiotic-ligand recognition should prove valuable in the rational design of improved drugs. We have determined the X-ray crystal structure of the complex of vancomycin with N-acetyl-D-Ala-D-Ala, a mimic of the natural muramyl peptide target, and refined this structure at a resolution of 1.3 A to R and R(free) values of 0.172 and 0.195, respectively. The crystal asymmetric unit contains three back-back vancomycin dimers; two of these dimers participate in ligand-mediated face-face interactions that produce an infinite chain of molecules running throughout the crystal. The third dimer packs against the side of a face-face interface in a tight "side-side" interaction that involves both polar contacts and burial of hydrophobic surface. The trimer of dimers found in the asymmetric unit is essentially identical to complexes seen in three other crystal structures of glycopeptide antibiotics complexed with peptide ligands. These four structures are derived from crystals belonging to different space groups, suggesting that the trimer of dimers may not be simply a crystal packing artifact and prompting us to ask if ligand-mediated oligomerization could be observed in solution. Using size-exclusion chromatography, dynamic light scattering, and small-angle X-ray scattering, we demonstrate that vancomycin forms discrete supramolecular complexes in the presence of tripeptide ligands. Size estimates for these complexes are consistent with assemblies containing four to six vancomycin monomers.
Loll
Patrick J
PJ
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Pat.Loll@Drexel.edu
Derhovanessian
Ariss
A
Shapovalov
Maxim V
MV
Kaplan
Jeffrey
J
Yang
Lin
L
Axelsen
Paul H
PH
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D053838:Scattering, Small Angle; D012996:Solutions; D014640:Vancomycin / Q000737:chemistry*; D014961:X-Ray Diffraction
D000900:Anti-Bacterial Agents; D008024:Ligands; D012996:Solutions; D014640:Vancomycin