Structural insights into the mechanism of translational inhibition by the fungicide sordarin.

ABSTRACT

The translational machinery has been found to be the target for a number of antibiotics. One such antibiotic sordarin selectively inhibits fungal translation by impairing the function of elongation factor 2 (eEF2) while being ineffective to higher eukaryotes. Surprisingly, sordarin is not even equally effective in impairing translation for all fungal species. The binding cavity of sordarin on eEF2 has been localized by X-ray crystallographic study and its unique specificity towards sordarin has been attributed to the species specific substitutions within a stretch of amino acids (sordarin specificity region, SSR) at the entrance of the cavity. In this study, we have analyzed the sordarin-binding cavity of eEF2 from different species both in isolated and ribosome-bound forms in order to decipher the mechanism of sordarin binding selectivity. Our results reveal that the molecular architecture as well as the microenvironment of the sordarin-binding cavity changes significantly from one species to another depending on the species specific substitutions within the cavity. Moreover, eEF2 binding to ribosome aggravates the effects of these substitutions. Thus, this study, while shedding light on the molecular mechanism underpinning the selective inhibitory effects of sordarin, will also be a helpful guide for future studies aiming at developing novel antifungal drugs with broader spectrum of activity.