title: Exploring the active site of acyl homoserine lactones-dependent transcriptional regulators with bacterial quorum sensing modulators using molecular mechanics and docking studies.
abstract: A comparative molecular modelling study of acyl homoserine lactones-dependent transcriptional regulators (TraR, SdiA, LuxR and LasR) involved in bacterial quorum sensing (QS) revealed a high structural homology of their active site. Docking studies within the active site of TraR of fixed conformations obtained using molecular mechanics calculations showed that TraR, for which the crystalline structure is known, is a relevant model for the study of other protein-ligand interactions in the same protein family. Structure-activity relationships of AHLs derived QS modulators including carboxamides, sulfonamides and ureas were thus investigated. The results show that Tyr61, a residue conserved in the LuxR-proteins family, is involved in attractive interactions with aromatic carboxamide antagonists. Tyr53, Tyr61 and Asp70, conserved residues, are implicated in both the development of additional hydrogen bonds and attractive interactions with the N-sulfonyl homoserine lactones and AHLs derived ureas antagonists.
authors.affiliation: ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, université de Lyon, université Lyon 1, CNRS, UMR5246, Lyon F-69622, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Soulère
authors.forename: Marine
authors.initials: M
authors.lastname: Frezza
authors.forename: Yves
authors.initials: Y
authors.lastname: Queneau
authors.forename: Alain
authors.initials: A
authors.lastname: Doutheau
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D053038:Quorum Sensing; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014508:Urea / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000577:Amides; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D012097:Repressor Proteins; C097686:SdiA protein, bacteria; D013449:Sulfonamides; D015534:Trans-Activators; D014157:Transcription Factors; C064778:LuxR autoinducer binding proteins; C088386:homoserine lactone; D014508:Urea; D015107:4-Butyrolactone