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Title: Crystal structure of serratia fonticola Sfh-I: activation of the nucleophile in mono-zinc metallo-β-lactamases
Author: Fonseca, Fátima
Bromley, Elizabeth H. C.
Saavedra, Maria José
Correia, António
Spencer, James
Keywords: Metallo-β-lactamase
Antibiotic resistance
Zinc β-lactamase
X-ray crystallography
Catalytic mechanism
Issue Date: 2011
Publisher: Elsevier
Abstract: Metallo-β-lactamases (MBLs) or class B β-lactamases are zinc-dependent enzymes capable of inactivating almost all classes of β-lactam antibiotics. To date, no MBL inhibitors are available for clinical use. Of the three MBL subclasses, B2 enzymes, unlike those from subclasses B1 and B3, are fully active with one zinc ion bound and possess a narrow spectrum of activity, hydrolyzing carbapenem substrates almost exclusively. These remain the least studied MBLs. Sfh-I, originally identified from the aquatic bacterium Serratia fonticola UTAD54, is a divergent member of this group. Previous B2 MBL structures, available only for the CphA enzyme from Aeromonas hydrophila, all contain small molecules bound in their active sites. In consequence, the mechanism by which these enzymes activate the water nucleophile required for β-lactam hydrolysis remains to be unambiguously established. Here we report crystal structures of Sfh-I as a complex with glycerol and in the unliganded form, revealing for the first time the disposition of water molecules in the B2 MBL active site. Our data indicate that the hydrolytic water molecule is activated by His118 rather than by Asp120 and/or zinc. Consistent with this proposal, we show that the environment of His118 in B2 MBLs is distinct from that of the B1 and B3 enzymes, where this residue acts as a zinc ligand, and offer a structure-based mechanism for β-lactam hydrolysis by these enzymes.
Peer review: yes
ISSN: 0022-2836
Appears in Collections:CESAM - Artigos
DBio - Artigos

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