title: Structure of apo- and monometalated forms of NDM-1--a highly potent carbapenem-hydrolyzing metallo-β-lactamase.
abstract: The New Delhi Metallo-β-lactamase (NDM-1) gene makes multiple pathogenic microorganisms resistant to all known β-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 β-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-β-lactamase. This site is capable of accommodating many β-lactam substrates by having many of the catalytic residues on flexible loops, which explains the observed extended spectrum activity of this zinc dependent β-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.
authors.affiliation: Midwest Center for Structural Genomics and Structural Biology Center, Biosciences, Argonne National Laboratory, Argonne, Illinois, United States of America.
authors.forename: Youngchang
authors.initials: Y
authors.lastname: Kim
authors.forename: Christine
authors.initials: C
authors.lastname: Tesar
authors.forename: Joseph
authors.initials: J
authors.lastname: Mire
authors.forename: Robert
authors.initials: R
authors.lastname: Jedrzejczak
authors.forename: Andrew
authors.initials: A
authors.lastname: Binkowski
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Babnigg
authors.forename: James
authors.initials: J
authors.lastname: Sacchettini
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
mesh_terms: D015780:Carbapenems / Q000378:metabolism*; D002850:Chromatography, Gel; D004755:Enterobacteriaceae / Q000201:enzymology; D017433:Protein Structure, Secondary; D014961:X-Ray Diffraction; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D015780:Carbapenems; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1