Molecular Basis for the Recognition of Structurally Distinct Autoinducer Mimics by the Pseudomonas aeruginosa LasR Quorum-Sensing Signaling Receptor

Journal Article · Tue Jan 12 04:00:00 EST 2010 · Chem. Biol.

DOI:https://doi.org/10.1016/j.chembiol.2009.09.001· OSTI ID:1006059

Zou, Yaozhong; Nair, Satish K

The human pathogen Pseudomonas aeruginosa coordinates the expression of virulence factors using quorum sensing, a signaling cascade triggered by the activation of signal receptors by small-molecule autoinducers. These homoserine lactone autoinducers stabilize their cognate receptors and activate their functions as transcription factors. Because quorum sensing regulates the progression of infection and host immune resistance, significant efforts have been devoted toward the identification of small molecules that disrupt this process. Screening efforts have identified a class of triphenyl compounds that are structurally distinct from the homoserine lactone autoinducer, yet interact specifically and potently with LasR receptor to modulate quorum sensing (Muh et al., 2006a). Here we present the high-resolution crystal structures of the ligand binding domain of LasR in complex with the autoinducer N-3-oxo-dodecanoyl homoserine lactone (1.4 {angstrom} resolution), and with the triphenyl mimics TP-1, TP-3, and TP-4 (to between 1.8 {angstrom} and 2.3 {angstrom} resolution). These crystal structures provide a molecular rationale for understanding how chemically distinct compounds can be accommodated by a highly selective receptor, and provide the framework for the development of novel quorum-sensing regulators, utilizing the triphenyl scaffold.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1006059
• Journal Information: Chem. Biol., Journal Name: Chem. Biol. Journal Issue: (9) ; 09, 2009 Vol. 16; ISSN 1074-5521
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
LACTONES
PATHOGENS
PSEUDOMONAS
RESOLUTION
TRANSCRIPTION FACTORS
VIRULENCE