摘要
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 the antimalarials that target 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 that DHFR-TS is a viable herbicide target.
基金
supported in part by Oracle Cloud credits and related resources provided by the Oracle for Research program
supported by an Australian Research Council Discovery Project to J.S.M.,K.A.S.,and J.H.(DP190101048)
an Australian Research Council Discovery Early Career Researcher award to J.H.(DE180101445)
an Australian Research Council Linkage Infrastructure,Equipment and Facilities grant to C.S.B.and J.S.M.(LE230100156).
