Structural insights into a plant-conserved DHFR-TS reveal a selective herbicide target
Date
2025
Authors
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.
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Advisors
Journal Title
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Journal article
Citation
Molecular Plant, 2025; 18(8):1294-1309
Statement of Responsibility
Joel Haywood, Karen J. Breese, Daniel P. McDougal, Callum Verdonk, Abigail Partridge, Adrian F. Lo, Jingjing Zhang, Wen-Chao Yang, John B. Bruning, Kevin J. Saliba, Charles S. Bond, Keith A. Stubbs, and Joshua S. Mylne
Conference Name
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-manage ment practices are vital to mitigate this threat. As the antimalarials that target the bifunctional enzyme hydrofolate 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 sults suggest that DHFR-TS is a viable herbicide target.
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© 2025 CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, and Chinese Society for Plant Biology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.