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PDBsum entry 1c0r
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References listed in PDB file
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Key reference
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Title
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Vancomycin binding to low-Affinity ligands: delineating a minimum set of interactions necessary for high-Affinity binding.
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Authors
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P.J.Loll,
J.Kaplan,
B.S.Selinsky,
P.H.Axelsen.
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Ref.
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J Med Chem, 1999,
42,
4714-4719.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Headers
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