8SK2
X-ray structure of the NDM-4 beta-lactamase from Klebsiella pneumonia, apo form
Summary for 8SK2
| Entry DOI | 10.2210/pdb8sk2/pdb |
| Descriptor | Metallo-beta-lactamase type 2, ZINC ION, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | beta-lactamase, antibiotic resistance, metallo-enzyme, hydrolase |
| Biological source | Klebsiella pneumoniae |
| Total number of polymer chains | 1 |
| Total formula weight | 28633.15 |
| Authors | Thoden, J.B.,Holden, H.M. (deposition date: 2023-04-18, release date: 2023-08-23, Last modification date: 2023-10-04) |
| Primary citation | Thoden, J.B.,Benin, B.M.,Priebe, A.,Shin, W.S.,Muthyala, R.,Sham, Y.Y.,Holden, H.M. Characterization of a novel inhibitor for the New Delhi metallo-beta-lactamase-4: Implications for drug design and combating bacterial drug resistance. J.Biol.Chem., 299:105135-105135, 2023 Cited by PubMed Abstract: The bacterial metallo-β-lactamases (MBLs) catalyze the inactivation of β-lactam antibiotics. Identifying novel pharmacophores remains crucial for the clinical development of additional MBL inhibitors. Previously, 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid, hereafter referred to as 1,2-HPT-6-COOH, was reported as a low cytotoxic nanomolar β-lactamase inhibitor of Verona-integron-encoded metallo-β-lactamase 2, capable of rescuing β-lactam antibiotic activity. In this study, we explore its exact mechanism of inhibition and the extent of its activity through structural characterization of its binding to New Delhi metallo-β-lactamase 4 (NDM-4) and its inhibitory activity against both NDM-1 and NDM-4. Of all the structure-validated MBL inhibitors available, 1,2-HPT-6-COOH is the first discovered compound capable of forming an octahedral coordination sphere with Zn2 of the binuclear metal center. This unexpected mechanism of action provides important insight for the further optimization of 1,2-HPT-6-COOH and the identification of additional pharmacophores for MBL inhibition. PubMed: 37549809DOI: 10.1016/j.jbc.2023.105135 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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