Abstract
Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems; however, no effective inhibitors are currently clinically available. MBLs are classified into three subclasses: B1, B2, and B3. Although the amino acid sequences of MBLs are varied, their overall scaffold is well conserved. In this study, we systematically studied the primary sequences and crystal structures of all subclasses of MBLs, especially the core scaffold, the zinc-coordinating residues in the active site, and the substrate-binding pocket. We presented the conserved structural features of MBLs in the same subclass and the characteristics of MBLs of each subclass. The catalytic zinc ions are bound with four loops from the two central β-sheets in the conserved αβ/βα sandwich fold of MBLs. The three external loops cover the zinc site(s) from the outside and simultaneously form a substrate-binding pocket. In the overall structure, B1 and B2 MBLs are more closely related to each other than they are to B3 MBLs. However, B1 and B3 MBLs have two zinc ions in the active site, while B2 MBLs have one. The substrate-binding pocket is different among all three subclasses, which is especially important for substrate specificity and drug resistance. Thus far, various classes of β-lactam antibiotics have been developed to have modified ring structures and substituted R groups. Currently available structures of β-lactam-bound MBLs show that the binding of β-lactams is well conserved according to the overall chemical structure in the substrate-binding pocket. Besides β-lactam substrates, B1 and cross-class MBL inhibitors also have distinguished differences in the chemical structure, which fit well to the substrate-binding pocket of MBLs within their inhibitory spectrum. The systematic structural comparison among B1, B2, and B3 MBLs provides in-depth insight into their substrate specificity, which will be useful for developing a clinical inhibitor targeting MBLs.
Highlights
The increasing incidence of multidrug-resistant (MDR) bacteria is a global health concern (Laxminarayan et al, 2013; Berendonk et al, 2015; Lee et al, 2016). β-lactams constitute 60% of current antibiotics; far, they have been the most applicable and useful class of antibiotics (Ozturk et al, 2015)
Members of the B1 subclass exist in large numbers and contain many clinically important MDLs, such as NDMs, Verona integrin-encoded MBLs (VIMs), imipenemases (IMPs), and German imipenemases (GIMs)
All the zinc-coordinating residues exist at the tip of the secondary structures of the helix and strand; they are tightly wrapped in the center with three external loops from the outside
Summary
The increasing incidence of multidrug-resistant (MDR) bacteria is a global health concern (Laxminarayan et al, 2013; Berendonk et al, 2015; Lee et al, 2016). β-lactams constitute 60% of current antibiotics; far, they have been the most applicable and useful class of antibiotics (Ozturk et al, 2015). Many MBLs from the three different subclasses have been studied in parallel, these comparisons were mainly related to the catalytic zinc ion(s) and the sequence and structure of the coordinating residues. The RMSD values comparing NDM-1 for B2 and B3 MBLs were 1.42 Å in approximately 195 residues and 2.25 Å in approximately 176 residues, respectively (Supplementary Tables 2–5) These results show that the overall scaffold is more similar between B1 and B2 MBLs than between B3 MBLs and the other two subclasses
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