3P2H

Crystal structure of TofI in a ternary complex with an inhibitor and MTA

Summary for 3P2H

• Entry DOI: 10.2210/pdb3p2h/pdb
• Related: 3P2F
• Descriptor: AHL synthase, 5'-DEOXY-5'-METHYLTHIOADENOSINE, N-(3-oxocyclohex-1-en-1-yl)octanamide, ... (4 entities in total)
• Functional Keywords: synthase, acyl-acp binding, sam binding, signaling protein-inhibitor-mta complex, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Burkholderia glumae (Pseudomonas glumae)
• Total number of polymer chains: 1
• Total formula weight: 22753.93

Authors

Yu, S.,Rhee, S. (deposition date: 2010-10-02, release date: 2011-07-06, Last modification date: 2024-03-20)

Primary citation

Chung, J.,Goo, E.,Yu, S.,Choi, O.,Lee, J.,Kim, J.,Kim, H.,Igarashi, J.,Suga, H.,Moon, J.S.,Hwang, I.,Rhee, S.
Small-molecule inhibitor binding to an N-acyl-homoserine lactone synthase
Proc.Natl.Acad.Sci.USA, 108:12089-12094, 2011

PubMed 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.

PubMed: 21730159
DOI: 10.1073/pnas.1103165108

Experimental method

X-RAY DIFFRACTION (2 Å)