Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
Protein Sci. 2011 Sep;20(9):1484-91. doi: 10.1002/pro.697. Epub 2011 Aug 2.
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.
β-内酰胺类抗生素是目前应用最广泛的抗生素类别，对人类健康产生了巨大影响。令人不安的是，一种名为新德里金属β-内酰胺酶-1（NDM-1）的酶可以使肠杆菌科细菌对几乎所有β-内酰胺类抗生素（包括碳青霉烯类抗生素）产生完全耐药性。我们已经解析了肺炎克雷伯菌apo-NDM-1 的晶体结构，分辨率达到 2.1 Å。从结构上看，NDM-1 具有一个扩展的活性位点和独特的静电分布，我们推测这导致了更广泛的底物特异性。此外，NDM-1 在与底物结合时会发生重要的构象变化。这些变化在金属β-内酰胺酶中尚未观察到，可能会直接影响底物识别和催化。
