Crystal structures of the complexes between vancomycin and cell-wall precursor analogs |
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Authors: | Nitanai Yasushi Kikuchi Takanori Kakoi Kouji Hanamaki Shinji Fujisawa Ikuhide Aoki Katsuyuki |
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Institution: | 1 Structural Biophysics Laboratory, RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo, Hyogo 679-5148, Japan 2 Department of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi 441-8580, Japan |
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Abstract: | The crystal structures of three vancomycin complexes with two vancomycin-sensitive cell-wall precursor analogs (diacetyl-Lys-D-Ala-D-Ala and acetyl-D-Ala-D-Ala) and a vancomycin-resistant cell-wall precursor analog (diacetyl-Lys-D-Ala-D-lactate) were determined at atomic resolutions of 1.80 A, 1.07 A, and 0.93 A, respectively. These structures not only reconfirm the "back-to-back" dimerization of vancomycin monomers and the ligand-binding scheme proposed by previous experiments but also show important structural features of strategies for the generation of new glycopeptide antibiotics. These structural features involve a water-mediated antibiotic-ligand interaction and supramolecular structures such as "side-by-side" arranged dimer-to-dimer structures, in addition to ligand-mediated and "face-to-face" arranged dimer-to-dimer structures. In the diacetyl-Lys-D-Ala-D-lactate complex, the interatomic O...O distance between the carbonyl oxygen of the fourth residue of the antibiotic backbone and the ester oxygen of the D-lactate moiety of the ligand is clearly longer than the corresponding N-H...O hydrogen-bonding distance observed in the two other complexes due to electrostatic repulsion. In addition, two neighboring hydrogen bonds are concomitantly lengthened. These observations provide, at least in part, a molecular basis for the reduced antibacterial activity of vancomycin toward vancomycin-resistant bacteria with cell-wall precursors terminating in -D-Ala-D-lactate. |
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Keywords: | VRE vancomycin-resistant enterococci DALAA d-Ala-d-Ala" target="_blank">diacetyl-Lys-d-Ala-d-Ala DALALac d-Ala-d-lactate" target="_blank">diacetyl-Lys-d-Ala-d-lactate NAAA d-Ala-d-Ala" target="_blank">N-acetyl-d-Ala-d-Ala PDB Protein Data Bank MR molecule replacement |
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