8DAE

Arabidopsis thaliana bifunctional dihydrofolate reductase-thymidylate synthase

Summary for 8DAE

• Entry DOI: 10.2210/pdb8dae/pdb
• Descriptor: Bifunctional dihydrofolate reductase-thymidylate synthase 1 (2 entities in total)
• Functional Keywords: apo, transferase, oxidoreductase
• Biological source: Arabidopsis thaliana (thale cress)
• Total number of polymer chains: 1
• Total formula weight: 60276.37

Authors

Bond, C.S.,Haywood, J. (deposition date: 2022-06-13, release date: 2023-06-21, Last modification date: 2026-02-04)

Primary citation

Haywood, J.,Breese, K.J.,McDougal, D.P.,Verdonk, C.,Partridge, A.,Lo, A.F.,Zhang, J.,Yang, W.C.,Bruning, J.B.,Saliba, K.J.,Bond, C.S.,Stubbs, K.A.,Mylne, J.S.
Structural insights into a plant-conserved DHFR-TS reveal a selective herbicide target.
Mol Plant, 18:1294-1309, 2025

PubMed 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 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.

PubMed: 40598768
DOI: 10.1016/j.molp.2025.06.016

Experimental method

X-RAY DIFFRACTION (2 Å)