Crystal structure of New Delhi metallo-β-lactamase reveals molecular basis for antibiotic resistance

Protein Sci. 2011 Sep;20(9):1484-91. doi: 10.1002/pro.697. Epub 2011 Aug 2.

Abstract

β-Lactams are the most commonly prescribed class of antibiotics and have had an enormous impact on human health. Thus, it is disquieting that an enzyme called New Delhi metallo-β-lactamase-1 (NDM-1) can confer Enterobacteriaceae with nearly complete resistance to all β-lactam antibiotics including the carbapenams. We have determined the crystal structure of Klebsiella pneumoniae apo-NDM-1 to 2.1-Å resolution. From the structure, we see that NDM-1 has an expansive active site with a unique electrostatic profile, which we propose leads to a broader substrate specificity. In addition, NDM-1 undergoes important conformational changes upon substrate binding. These changes have not been previously observed in metallo-β-lactamase enzymes and may have a direct influence on substrate recognition and catalysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Crystallography, X-Ray / methods*
  • Drug Resistance, Microbial / genetics
  • Drug Resistance, Microbial / physiology
  • Klebsiella pneumoniae / enzymology
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • beta-Lactamases / chemistry*
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism

Substances

  • Bacterial Proteins
  • beta-Lactamases
  • beta-lactamase NDM-1