30EJ
2-heptyl-4(1H)-quinolone synthase PqsBC in complex with compound 33
This is a non-PDB format compatible entry.
Summary for 30EJ
| Entry DOI | 10.2210/pdb30ej/pdb |
| Descriptor | 2-heptyl-4(1H)-quinolone synthase subunit PqsC, 2-heptyl-4(1H)-quinolone synthase subunit PqsB, 1,2-ETHANEDIOL, ... (6 entities in total) |
| Functional Keywords | quorum sensing, inhibitor, pseudomonas aeruginosa, biosynthetic protein |
| Biological source | Pseudomonas aeruginosa PAO1 More |
| Total number of polymer chains | 8 |
| Total formula weight | 284856.79 |
| Authors | |
| Primary citation | Ding, W.,Borgert, S.R.,Blankenfeldt, W.,Sieber, S.A. Chemical Inhibition of Pyocyanin Biosynthesis Attenuates Virulence of Pseudomonas aeruginosa. Angew.Chem.Int.Ed.Engl., 2026 Cited by PubMed Abstract: Anti-virulence strategies that disarm bacterial pathogenicity without affecting viability offer a promising alternative to traditional antibiotics by reducing selective pressure for resistance. However, in Gram-negative bacteria such as Pseudomonas aeruginosa, the double-layered cell envelope limits intracellular access of small-molecule inhibitors. Here, we screened a structurally diverse library of virulence inhibitors, previously established as pathoblockers in Gram-positive bacteria, and identified a potent β-lactone inhibitor of pyocyanin production. Activity-based protein profiling revealed PqsC, an intracellular enzyme involved in Pseudomonas quinolone signal (PQS) quorum sensing, as the primary molecular target. Accordingly, global proteomic analysis revealed widespread dysregulation of enzymes associated with the pyocyanin biosynthetic pathway. Biochemical assays confirmed inhibition of recombinant PqsBC, while intact protein mass spectrometry and site-directed mutagenesis established active site Cys129 as the covalent binding site. X-ray crystallography of the inhibited complex revealed a covalent binding mode. Subsequent virtual screening identified a chloroacetamide scaffold that exhibited enhanced potency and a well-defined binding mode. Importantly, supernatants from treated bacterial cultures showed reduced cytotoxicity toward mammalian cells, consistent with attenuated virulence. Collectively, this study identifies novel covalent inhibitors of PqsC and provides a mechanistic framework for the development of pathoblockers against P. aeruginosa. PubMed: 42935304DOI: 10.1002/anie.1294720 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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