Journal article
Vancomycin Forms Ligand-Mediated Supramolecular Complexes
Journal of molecular biology, v 385(1)
2009
PMID: 18983853
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 Å 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.
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Details
- Title
- Vancomycin Forms Ligand-Mediated Supramolecular Complexes
- Creators
- Patrick J Loll - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th St., MS 497, Philadelphia, PA 19102, USAAriss Derhovanessian - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USAMaxim V Shapovalov - Graduate Program in Biochemistry, Drexel University College of Medicine, Philadelphia, PA 19102, USAJeffrey Kaplan - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USALin Yang - National Synchrotron Light Source, Brookhaven National Laboratory, Upton, NY 11973, USAPaul H Axelsen - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Publication Details
- Journal of molecular biology, v 385(1)
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000262870200020
- Scopus ID
- 2-s2.0-57749191948
- Other Identifier
- 991014878174404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology