Structure of the Pseudomonas aeruginosa acyl-homoserinelactone synthase LasI
Article first published online: 9 JUL 2004
Volume 53, Issue 4, pages 1135–1146, August 2004
How to Cite
Gould, T. A., Schweizer, H. P. and Churchill, M. E. A. (2004), Structure of the Pseudomonas aeruginosa acyl-homoserinelactone synthase LasI. Molecular Microbiology, 53: 1135–1146. doi: 10.1111/j.1365-2958.2004.04211.x
- Issue published online: 9 JUL 2004
- Article first published online: 9 JUL 2004
- Accepted 15 April, 2004.
The LasI/LasR quorum-sensing system plays a pivotal role in virulence gene regulation of the opportunistic human pathogen, Pseudomonas aeruginosa. Here we report the crystal structure of the acyl-homoserine lactone (AHL) synthase LasI that produces 3-oxo-C12-AHL from the substrates 3-oxo-C12-acyl-carrier protein (acyl-ACP) and S-adenosyl-L-methionine. The LasI six-stranded beta sheet platform, buttressed by three alpha helices, forms a V-shaped substrate-binding cleft that leads to a tunnel passing through the enzyme that can accommodate the acyl-chain of acyl-ACP. This tunnel places no apparent restriction on acyl-chain length, in contrast to a restrictive hydrophobic pocket seen in the AHL-synthase EsaI. Interactions of essential conserved N-terminal residues, Arg23, Phe27 and Trp33, suggest that the N-terminus forms an enclosed substrate-binding pocket for S-adenosyl-L-methionine. Analysis of AHL-synthase surface residues identified a binding site for acyl-ACP, a role that was supported by in vivo reporter assay analysis of the mutated residues, including Arg154 and Lys150. This structure and the novel explanation of AHL-synthase acyl-chain-length selectivity promise to guide the design of Pseudomonas aeruginosa-specific quorum-sensing inhibitors as antibacterial agents.