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19 F-NMR Reveals the Role of Mobile Loops in Product and Inhibitor Binding by the Sao Paulo Metallo-?-Lactamase.

ABSTRACT: Resistance to ?-lactam antibiotics mediated by metallo-?-lactamases (MBLs) is a growing problem. We describe the use of protein-observe 19 F-NMR (PrOF?NMR) to study the dynamics of the São Paulo MBL (SPM-1) from ?-lactam-resistant Pseudomonas aeruginosa. Cysteinyl variants on the ?3 and L3 regions, which flank the di-ZnII active site, were selectively 19 F-labeled using 3-bromo-1,1,1-trifluoroacetone. The PrOF?NMR results reveal roles for the mobile ?3 and L3 regions in the binding of both inhibitors and hydrolyzed ?-lactam products to SPM-1. These results have implications for the mechanisms and inhibition of MBLs by ?-lactams and non-?-lactams and illustrate the utility of PrOF?NMR for efficiently analyzing metal chelation, identifying new binding modes, and studying protein binding from a mixture of equilibrating isomers.

SUBMITTER: Abboud MI 

PROVIDER: S-EPMC5396265 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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<sup>19</sup> F-NMR Reveals the Role of Mobile Loops in Product and Inhibitor Binding by the São Paulo Metallo-β-Lactamase.

Abboud Martine I MI   Hinchliffe Philip P   Brem Jürgen J   Macsics Robert R   Pfeffer Inga I   Makena Anne A   Umland Klaus-Daniel KD   Rydzik Anna M AM   Li Guo-Bo GB   Spencer James J   Claridge Timothy D W TD   Schofield Christopher J CJ  

Angewandte Chemie (International ed. in English) 20170302 14

Resistance to β-lactam antibiotics mediated by metallo-β-lactamases (MBLs) is a growing problem. We describe the use of protein-observe <sup>19</sup> F-NMR (PrOF NMR) to study the dynamics of the São Paulo MBL (SPM-1) from β-lactam-resistant Pseudomonas aeruginosa. Cysteinyl variants on the α3 and L3 regions, which flank the di-Zn<sup>II</sup> active site, were selectively <sup>19</sup> F-labeled using 3-bromo-1,1,1-trifluoroacetone. The PrOF NMR results reveal roles for the mobile α3 and L3 reg  ...[more]

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