5Y6E
VIM-2 metallo-beta-lactamase in complex with (R)-2-(4-hydroxyphenyl)-2-((S)-3-mercapto-2-methylpropanamido)acetic acid (compound 12)
Summary for 5Y6E
| Entry DOI | 10.2210/pdb5y6e/pdb |
| Descriptor | Beta-lactamase class B VIM-2, ZINC ION, (2R)-2-(4-hydroxyphenyl)-2-[[(2S)-2-methyl-3-sulfanyl-propanoyl]amino]ethanoic acid, ... (5 entities in total) |
| Functional Keywords | metallo-beta-lactamase vim-2, hydrolase |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 2 |
| Total formula weight | 50474.07 |
| Authors | Li, G.-B. (deposition date: 2017-08-11, release date: 2018-01-24, Last modification date: 2023-11-22) |
| Primary citation | Liu, S.,Jing, L.,Yu, Z.-J.,Wu, C.,Zheng, Y.,Zhang, E.,Chen, Q.,Yu, Y.,Guo, L.,Wu, Y.,Li, G.-B. ((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-beta-lactamase inhibitors: Synthesis, kinetic and crystallographic studies. Eur J Med Chem, 145:649-660, 2018 Cited by PubMed Abstract: The emergence and global spread of metallo-β-lactamase (MBL) mediated resistance to almost all β-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis. PubMed: 29353720DOI: 10.1016/j.ejmech.2018.01.032 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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