8GPD
Crystal structure of NDM-1 at pH5.5 (Succinate) in complex with hydrolyzed penicillin V
Summary for 8GPD
| Entry DOI | 10.2210/pdb8gpd/pdb |
| Descriptor | Metallo beta lactamase NDM-1, ZINC ION, (2R,4S)-5,5-dimethyl-2-[(1R)-2-oxidanyl-2-oxidanylidene-1-(2-phenoxyethanoylamino)ethyl]-1,3-thiazolidine-4-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | hydrolase |
| Biological source | Klebsiella pneumoniae |
| Total number of polymer chains | 2 |
| Total formula weight | 58092.40 |
| Authors | |
| Primary citation | Shi, X.,Dai, Y.,Lan, Z.,Wang, S.,Cui, L.,Xiao, C.,Zhao, K.,Li, X.,Liu, W.,Zhang, Q. Interplay between the beta-lactam side chain and an active-site mobile loop of NDM-1 in penicillin hydrolysis as a potential target for mechanism-based inhibitor design. Int.J.Biol.Macromol., 262:130041-130041, 2024 Cited by PubMed Abstract: Metallo-β-lactamases (MβLs) stand as significant resistant mechanism against β-lactam antibiotics in Gram-negative bacteria. The worldwide dissemination of New Delhi metallo-β-lactamases (NDMs) intensifies antimicrobial resistance, posing severe threats to human health due to the absence of inhibitors available in clinical therapy. L3, a flexible β-hairpin loop flanking the active site in MβLs, has been proven to wield influence over the reaction process by assuming a crucial role in substrate recognition and intermediate stabilization. In principle, it potentially retards product release from the enzyme, consequently reducing the overall turnover rate although the details regarding this aspect remain inadequately elucidated. In this study, we crystallized NDM-1 in complex with three penicillin substrates, conducted molecular dynamics simulations, and measured the steady-state kinetic parameters. These analyses consistently unveiled substantial disparities in their interactions with loop L3. We further synthesized a penicillin V derivative with increased hydrophobicity in the R1 side chain and co-crystallized it with NDM-1. Remarkably, this compound exhibited much stronger dynamic interplay with L3 during molecular dynamics simulation, showed much lower K and k values, and demonstrated moderate inhibitory capacity to NDM-1 catalyzed meropenem hydrolysis. The data presented here may provide a strategic approach for designing mechanism-based MβL inhibitors focusing on structural elements external to the enzyme's active center. PubMed: 38336327DOI: 10.1016/j.ijbiomac.2024.130041 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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