Vancomycin Forms Ligand-Mediated Supramolecular Complexes

JOURNAL OF MOLECULAR BIOLOGY

卷:385

Article

Loll, Patrick J.¹  Derhovanessian, Ariss²  Shapovalov, Maxim V.³  Kaplan, Jeffrey²  Yang, Lin⁴  Axelsen, Paul H.² 

[1] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19102 USA

[2] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA

[3] Drexel Univ, Coll Med, Grad Program Biochem, Philadelphia, PA 19102 USA

[4] Brookhaven Natl Lab, Natl Synchrotron Light Source, Upton, NY 11973 USA

关键词: X-ray crystallography;    glycopeptide antibiotics;    antibiotic resistance;    vancomycin;    small-angle X-ray scattering;   

DOI  :  10.1016/j.jmb.2008.10.049

来源: Elsevier

【 摘 要 】

The emergence of resistance to vancomycin and related glycopeptide antibiotics is spurring efforts to develop new antimicrobial therapeutics. Hgh-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 13 angstrom to R and R-free values of 0.172 and 0.195, respectively. The crystal asymmetric unit contains three back-back vancomycin dinners; 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. (C) 2008 Elsevier Ltd. All rights reserved.

【 授权许可】

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