Structure of apo- and monometalated forms of NDM-1A highly potent carbapenemhydrolyzing metallo-β-lactamase. PLoS One 2011

The New Delhi Metallo-b-lactamase (NDM-1) gene makes multiple pathogenic microorganisms resistant to all known b-lactam antibiotics. The rapid emergence of NDM-1 has been linked to mobile plasmids that move between different strains resulting in world-wide dissemination. Biochemical studies revealed that NDM-1 is capable of efficiently hydrolyzing a wide range of b-lactams, including many carbapenems considered as ‘‘last resort’ ’ antibiotics. The crystal structures of metal-free apo- and monozinc forms of NDM-1 presented here revealed an enlarged and flexible active site of class B1 metallo-b-lactamase. This site is capable of accommodating many b-lactam substrates by having many of the catalytic residues on flexible loops, which explains the observed extended spectrum activity of this zinc dependent b-lactamase. Indeed, five loops contribute ‘‘keg’ ’ residues in the active site including side chains involved in metal binding. Loop 1 in particular, shows conformational flexibility, apparently related to the acceptance and positioning of substrates for cleavage by a zinc-activated water molecule