title: Small-molecule inhibitor binding to an N-acyl-homoserine lactone synthase.
abstract: Quorum sensing (QS) controls certain behaviors of bacteria in response to population density. In gram-negative bacteria, QS is often mediated by N-acyl-L-homoserine lactones (acyl-HSLs). Because QS influences the virulence of many pathogenic bacteria, synthetic inhibitors of acyl-HSL synthases might be useful therapeutically for controlling pathogens. However, rational design of a potent QS antagonist has been thwarted by the lack of information concerning the binding interactions between acyl-HSL synthases and their ligands. In the gram-negative bacterium Burkholderia glumae, QS controls virulence, motility, and protein secretion and is mediated by the binding of N-octanoyl-L-HSL (C8-HSL) to its cognate receptor, TofR. C8-HSL is synthesized by the acyl-HSL synthase TofI. In this study, we characterized two previously unknown QS inhibitors identified in a focused library of acyl-HSL analogs. Our functional and X-ray crystal structure analyses show that the first inhibitor, J8-C8, binds to TofI, occupying the binding site for the acyl chain of the TofI cognate substrate, acylated acyl-carrier protein. Moreover, the reaction byproduct, 5'-methylthioadenosine, independently binds to the binding site for a second substrate, S-adenosyl-L-methionine. Closer inspection of the mode of J8-C8 binding to TofI provides a likely molecular basis for the various substrate specificities of acyl-HSL synthases. The second inhibitor, E9C-3oxoC6, competitively inhibits C8-HSL binding to TofR. Our analysis of the binding of an inhibitor and a reaction byproduct to an acyl-HSL synthase may facilitate the design of a new class of QS-inhibiting therapeutic agents.
authors: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Korea.
authors: Jiwoung
authors: J
authors: Chung
authors: Eunhye
authors: E
authors: Goo
authors: Sangheon
authors: S
authors: Yu
authors: Okhee
authors: O
authors: Choi
authors: Jeehyun
authors: J
authors: Lee
authors: Jinwoo
authors: J
authors: Kim
authors: Hongsup
authors: H
authors: Kim
authors: Jun
authors: J
authors: Igarashi
authors: Hiroaki
authors: H
authors: Suga
authors: Jae Sun
authors: JS
authors: Moon
authors: Ingyu
authors: I
authors: Hwang
authors: Sangkee
authors: S
authors: Rhee
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019117:Burkholderia / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005453:Fluorescence; D006714:Homoserine / Q000031:analogs & derivatives / Q000378:metabolism; D007783:Lactones / Q000378:metabolism; D011485:Protein Binding; D053038:Quorum Sensing / Q000502:physiology*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007783:Lactones; C085427:LuxI protein, Bacteria; C091088:N-octanoylhomoserine lactone; D014157:Transcription Factors; C088386:homoserine lactone; D006714:Homoserine; D012436:S-Adenosylmethionine; D015107:4-Butyrolactone