Dataset Information

A close look onto structural models and primary ligands of metallo-?-lactamases.

ABSTRACT: ?-Lactamases are hydrolytic enzymes capable of opening the ?-lactam ring of antibiotics such as penicillin, thus endowing the bacteria that produce them with antibiotic resistance. Of particular medical concern are metallo-?-lactamases (MBLs), with an active site built around coordinated Zn cations. MBLs are pan-reactive enzymes that can break down almost all classes of ?-lactams, including such last-resort antibiotics as carbapenems. They are not only broad-spectrum-reactive but are often plasmid-borne (e.g., the New Delhi enzyme, NDM), and can spread horizontally even among unrelated bacteria. Acquired MBLs are encoded by mobile genetic elements, which often include other resistance genes, making the microbiological situation particularly alarming. There is an urgent need to develop MBL inhibitors in order to rescue our antibiotic armory. A number of such efforts have been undertaken, most notably using the 3D structures of various MBLs as drug-design targets. Structure-guided drug discovery depends on the quality of the structures that are collected in the Protein Data Bank (PDB) and on the consistency of the information in dedicated ?-lactamase databases. We conducted a careful review of the crystal structures of class B ?-lactamases, concluding that the quality of these structures varies widely, especially in the regions where small molecules interact with the macromolecules. In a number of examples the interpretation of the bound ligands (e.g., inhibitors, substrate/product analogs) is doubtful or even incorrect, and it appears that in some cases the modeling of ligands was not supported by electron density. For ten MBL structures, alternative interpretations of the original diffraction data could be proposed and the new models have been deposited in the PDB. In four cases, these models, prepared jointly with the authors of the original depositions, superseded the previous deposits. This review emphasizes the importance of critical assessment of structural models describing key drug design targets at the level of the raw experimental data. Since the structures reviewed here are the basis for ongoing design of new MBL inhibitors, it is important to identify and correct the problems with ambiguous crystallographic interpretations, thus enhancing reproducibility in this highly medically relevant area.

SUBMITTER: Raczynska JE

PROVIDER: S-EPMC6260963 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A close look onto structural models and primary ligands of metallo-β-lactamases.

Raczynska Joanna E JE Shabalin Ivan G IG Minor Wladek W Wlodawer Alexander A Jaskolski Mariusz M

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 20180825

β-Lactamases are hydrolytic enzymes capable of opening the β-lactam ring of antibiotics such as penicillin, thus endowing the bacteria that produce them with antibiotic resistance. Of particular medical concern are metallo-β-lactamases (MBLs), with an active site built around coordinated Zn cations. MBLs are pan-reactive enzymes that can break down almost all classes of β-lactams, including such last-resort antibiotics as carbapenems. They are not only broad-spectrum-reactive but are often plasm ...[more]

PMID: 30466711

Similar Datasets

Project description:BACKGROUND: Genes conferring antibiotic resistance to groups of bacterial pathogens are cause for considerable concern, as many once-reliable antibiotics continue to see a reduction in efficacy. The recent discovery of the metallo ?-lactamase blaNDM-1 gene, which appears to grant antibiotic resistance to a variety of Enterobacteriaceae via a mobile plasmid, is one example of this distressing trend. The following work describes a computational analysis of pathogen-borne MBLs that focuses on the structural aspects of characterized proteins. RESULTS: Using both sequence and structural analyses, we examine residues and structural features specific to various pathogen-borne MBL types. This analysis identifies a linker region within MBL-like folds that may act as a discriminating structural feature between these proteins, and specifically resistance-associated acquirable MBLs. Recently released crystal structures of the newly emerged NDM-1 protein were aligned against related MBL structures using a variety of global and local structural alignment methods, and the overall fold conformation is examined for structural conservation. Conservation appears to be present in most areas of the protein, yet is strikingly absent within a linker region, making NDM-1 unique with respect to a linker-based classification scheme. Variability analysis of the NDM-1 crystal structure highlights unique residues in key regions as well as identifying several characteristics shared with other transferable MBLs. CONCLUSIONS: A discriminating linker region identified in MBL proteins is highlighted and examined in the context of NDM-1 and primarily three other MBL types: IMP-1, VIM-2 and ccrA. The presence of an unusual linker region variant and uncommon amino acid composition at specific structurally important sites may help to explain the unusually broad kinetic profile of NDM-1 and may aid in directing research attention to areas of this protein, and possibly other MBLs, that may be targeted for inactivation or attenuation of enzymatic activity.

Project description: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.

Dataset Information

A close look onto structural models and primary ligands of metallo-?-lactamases.

Publications

A close look onto structural models and primary ligands of metallo-β-lactamases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets