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Structural Study of Metal Binding and Coordination in Ancient Metallo-?-Lactamase PNGM-1 Variants.


ABSTRACT: The increasing incidence of community- and hospital-acquired infections with multidrug-resistant (MDR) bacteria poses a critical threat to public health and the healthcare system. Although ?-lactam antibiotics are effective against most bacterial infections, some bacteria are resistant to ?-lactam antibiotics by producing ?-lactamases. Among ?-lactamases, metallo-?-lactamases (MBLs) are especially worrisome as only a few inhibitors have been developed against them. In MBLs, the metal ions play an important role as they coordinate a catalytic water molecule that hydrolyzes ?-lactam rings. We determined the crystal structures of different variants of PNGM-1, an ancient MBL with additional tRNase Z activity. The variants were generated by site-directed mutagenesis targeting metal-coordinating residues. In PNGM-1, both zinc ions are coordinated by six coordination partners in an octahedral geometry, and the zinc-centered octahedrons share a common face. Structures of the PNGM-1 variants confirm that the substitution of a metal-coordinating residue causes the loss of metal binding and ?-lactamase activity. Compared with PNGM-1, subclass B3 MBLs lack one metal-coordinating residue, leading to a shift in the metal-coordination geometry from an octahedral to tetrahedral geometry. Our results imply that a subtle change in the metal-binding site of MBLs can markedly change their metal-coordination geometry and catalytic activity.

SUBMITTER: Park YS 

PROVIDER: S-EPMC7404133 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants.

Park Yoon Sik YS   Kim Tae Yeong TY   Park Hyunjae H   Lee Jung Hun JH   Nguyen Diem Quynh DQ   Hong Myoung-Ki MK   Lee Sang Hee SH   Kang Lin-Woo LW  

International journal of molecular sciences 20200712 14


The increasing incidence of community- and hospital-acquired infections with multidrug-resistant (MDR) bacteria poses a critical threat to public health and the healthcare system. Although β-lactam antibiotics are effective against most bacterial infections, some bacteria are resistant to β-lactam antibiotics by producing β-lactamases. Among β-lactamases, metallo-β-lactamases (MBLs) are especially worrisome as only a few inhibitors have been developed against them. In MBLs, the metal ions play a  ...[more]

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