Structural insights into a plant-conserved DHFR-TS reveal a selective herbicide target.

Abstract

Modern agricultural practices rely on herbicides to reduce yield losses. Herbicide-resistant weeds threaten herbicide utility and hence food security. New herbicide modes of action and integrated pest management practices are vital to mitigate this threat. As antimalarials targeting the bifunctional enzyme dihydrofolate reductase thymidylate synthase (DHFR-TS) have been shown to be herbicidal, DHFR-TS might represent a mode of action target for the development of herbicides. Here, we present the crystal structure of a DHFR-TS (AtDHFR-TS1) from the model dicot Arabidopsis thaliana. It shows a divergent DHFR active site and a linker domain that challenges previous classifications of bifunctional DHFR-TS proteins. This plant-conserved architecture enabled us to develop highly selective, herbicidal inhibitors of AtDHFR-TS1 over human DHFR and identify inhibitors with unique scaffolds via a large library virtual screen. These results suggest DHFR-TS is a viable herbicide target.