5LL7
Crystal structure of KPC-2 carbapenemase in complex with a phenyl boronic inhibitor.
Summary for 5LL7
| Entry DOI | 10.2210/pdb5ll7/pdb |
| Related | 5MGI |
| Descriptor | Beta-lactamase, (~{E})-3-[2-(dihydroxyboranyl)phenyl]prop-2-enoic acid, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | carbapenemase, beta-lactamase, phenyl boronic inhibitor, hydrolase |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 28769.10 |
| Authors | Vicario, M.,Celenza, G.,Bellio, P.,Perilli, M.G.,Tondi, D.,Cendron, L. (deposition date: 2016-07-26, release date: 2018-02-21, Last modification date: 2024-10-16) |
| Primary citation | Celenza, G.,Vicario, M.,Bellio, P.,Linciano, P.,Perilli, M.,Oliver, A.,Blazquez, J.,Cendron, L.,Tondi, D. Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step against Bacterial Resistance. Chemmedchem, 13:713-724, 2018 Cited by PubMed Abstract: The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last-resort carbapenems. In this study, we investigate the molecular recognition requirements in the KPC-2 active site by small phenylboronic acid derivatives. Four new phenylboronic acid derivatives were designed and tested against KPC-2. For the most active, despite their simple chemical structures, nanomolar affinity was achieved. The new derivatives restored susceptibility to meropenem in clinical strains overexpressing KPC-2. Moreover, no cytotoxicity was detected in cell-viability assays, which further validated the designed leads. Two crystallographic binary complexes of the best inhibitors binding KPC-2 were obtained at high resolution. Kinetic descriptions of slow binding, time-dependent inhibition, and interaction geometries in KPC-2 were fully investigated. This study will ultimately lead toward the optimization and development of more-effective KPC-2 inhibitors. PubMed: 29356380DOI: 10.1002/cmdc.201700788 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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