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Role of a solvent-exposed tryptophan in the recognition and binding of antibiotic substrates for a metallo-beta-lactamase

Academic Article
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Overview

authors

  • Huntley, J. J. A.
  • Fast, W.
  • Benkovic, S. J.
  • Wright, Peter
  • Dyson, Jane

publication date

  • July 2003

journal

  • Protein Science  Journal

abstract

  • Numerous X-ray crystal structures of the metallo-beta-lactamase from Bacteroides fragilis and related organisms show a beta-hairpin loop immediately adjacent to the active-site zinc atom(s). Both crystallographic and NMR information show that the end of this beta-hairpin loop, which contains a solvent exposed tryptophan residue, Trp49, is highly flexible in the absence of substrates or other ligands, giving rise in some of the X-ray structures to a lack of observable electron density in this region. We report an investigation of the role of this mobile, solvent-exposed tryptophan using site-directed mutagenesis, steady state kinetics measurements and characterization by NMR. Trp49 appears to have a role both in substrate binding and in promotion of catalysis. Substitution of this residue with a number of different side chains indicates that the binding interaction depends on the bulky hydrophobic and aromatic nature of the indole ring, which can provide relatively non-specific interactions with a variety of antibiotic substrates. In this way, the tryptophan at this position provides a large degree of the breadth of substrate specificity for the metallo-beta-lactamase. Previous studies established that the antibiotic binding site was sufficiently plastic that the derivatization of existing antibiotics is unlikely to result in the successful treatment of bacterial infections incorporating this resistance element. Rather, a more productive approach may be to design therapeutics directed towards this solvent-exposed tryptophan residue.

subject areas

  • Anti-Bacterial Agents
  • Bacteroides fragilis
  • Binding Sites
  • Cephalosporins
  • Enzyme Inhibitors
  • Kinetics
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Protein Conformation
  • Solvents
  • Substrate Specificity
  • Tryptophan
  • Zinc
  • beta-Lactamase Inhibitors
  • beta-Lactamases
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Research

keywords

  • enzyme kinetics
  • lactamase
  • lactamase inhibition
  • mutant
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Identity

PubMed Central ID

  • PMC2323931

International Standard Serial Number (ISSN)

  • 0961-8368

Digital Object Identifier (DOI)

  • 10.1110/ps.0305303

PubMed ID

  • 12824483
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Additional Document Info

start page

  • 1368

end page

  • 1375

volume

  • 12

issue

  • 7

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