PDBsum entry 1c0r

Antibiotic

PDB id: 1c0r

Contents

Ligands

MLU-OMZ-ASN-GHP-GHP-OMY-3FG ×2

BGC-RER ×2

LAC

Metals

_CL ×3

Waters ×45

PDB id:

1c0r

Name:

Antibiotic

Title:

Complex of vancomycin with d-lactic acid

Structure:

Vancomycin. Chain: a, b. Engineered: yes

Source:

Amycolatopsis orientalis. Organism_taxid: 31958

Resolution:

1.00Å R-factor: 0.114 R-free: 0.142

Authors:

P.J.Loll,J.Kaplan,B.Selinsky,P.H.Axelsen

Key ref:

P.J.Loll et al. (1999). Vancomycin binding to low-affinity ligands: delineating a minimum set of interactions necessary for high-affinity binding. J Med Chem, 42, 4714-4719. PubMed id: 10579833 DOI: 10.1021/jm990361t

Date:

20-Jul-99 Release date: 30-Jul-99

DOI no: 10.1021/jm990361t

J Med Chem 42:4714-4719 (1999)

PubMed id: 10579833

Vancomycin binding to low-affinity ligands: delineating a minimum set of interactions necessary for high-affinity binding.

P.J.Loll, J.Kaplan, B.S.Selinsky, P.H.Axelsen.

ABSTRACT

Bacterial resistance to vancomycin has been attributed to the loss of an intermolecular hydrogen bond between vancomycin and its peptidoglycan target when cell wall biosynthesis proceeds via depsipeptide intermediates rather than the usual polypeptide intermediates. To investigate the relative importance of this hydrogen bond to vancomycin binding, we have determined crystal structures at 1.0 A resolution for the vancomycin complexes with three ligands that mimic peptides and depsipeptides found in vancomycin-sensitive and vancomycin-resistant bacteria: N-acetylglycine, D-lactic acid, and 2-acetoxy-D-propanoic acid. These, in conjunction with structures that have been reported previously, indicate higher-affinity ligands elicit a structural change in the drug not seen with these low-affinity ligands. They also enable us to define a minimal set of drug-ligand interactions necessary to confer higher-affinity binding on a ligand. Most importantly, these structures point to factors in addition to the loss of an intermolecular hydrogen bond that must be invoked to explain the weaker affinity of vancomycin for depsipeptide ligands. These factors are important considerations for the design of vancomycin analogues to overcome vancomycin resistance.