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Bicer D, Matsuoka R, Moumbock AFA, Sukumar P, Suades A, Cheruvara H, Quigley A, Drew D, Pardon E, Steyaert J, Henderson PJF, Caffrey M, Griese JJ, Nji E
Nat Commun - (-) - [2025-12-04; online 2025-12-04]
Under conditions of extreme acidity, the lysine-specific permease, LysP, not only mediates the import of L-lysine it also interacts with the transcriptional regulator, CadC, to activate expression of the cadAB operon. This operon encodes the lysine decarboxylase, CadA, which converts lysine to cadaverine while consuming a cytoplasmic proton, and the antiporter, CadB, which exports protonated cadaverine in exchange for extracellular lysine. Together, these processes contribute to cytoplasmic pH homeostasis and support bacterial acid resistance - a mechanism essential for the survival of pathogenic bacteria in acidic host environments. Here, we present the cryo-EM structure of LysP from Pseudomonas aeruginosa in an inward-occluded conformation (3.2-5.3 Å resolution), bound to L-lysine and a nanobody. L-Lysine is coordinated by hydrophobic contacts, cation-π interactions, and by hydrogen bonding mostly with polar uncharged residues. Reconstitution of LysP into proteoliposomes confirms specific L-lysine transport, which is competitively inhibited by L-4-thialysine. These findings provide a structural framework for understanding selective lysine recognition and inhibition, with implications for antibacterial drug design.
PubMed 41345107
DOI 10.1038/s41467-025-66618-7
Crossref 10.1038/s41467-025-66618-7
pii: 10.1038/s41467-025-66618-7