Crystal structure determination of a chimeric FabF by XRD

Abstract

Beta-ketoacyl-acyl-carrier-protein synthase II, an important enzyme in biosynthesis of bacterial fatty acid, is an attractive target in antibacterial drug design. Platensimycin (PTM), produced by Streptomyces platensis, has a strong, broad-spectrum Gram-positive antibacterial activity by selectively targeting to FabF but exhibits no inhibition to the FabF from Streptomyces platensis (spFabF). To study the self-resistance mechanism within the PTM-producing strain and provide hint for development of novel antibiotics, it is imperative to solve the structure of spFabF and elucidate the difference between spFabF and other FabFs which are not resistant to PTM. To this end, we constructed four chimeric FabFs based on the sequence of spFabF and its homologous protein after the expression of wide-type spFabF was failed. The crystal structure of one chimera, js200FabF, of 91.2% sequence identity to spFabF, was solved. A structure comparison of js200FabF with a PTM-bound FabF suggested that three loops nearby the catalytic site might play key roles in preventing the binding of PTM to spFabF. The results provide an encouraging basis for further studies on the self-resistance mechanism and structure-based design of novel antibiotics targeting FabFs.