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

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dc.contributor.authorHaywood, J.
dc.contributor.authorBreese, K.J.
dc.contributor.authorMcDougal, D.P.
dc.contributor.authorVerdonk, C.
dc.contributor.authorPartridge, A.
dc.contributor.authorLo, A.F.
dc.contributor.authorZhang, J.
dc.contributor.authorYang, W.-C.
dc.contributor.authorBruning, J.B.
dc.contributor.authorSaliba, K.J.
dc.contributor.authorBond, C.S.
dc.contributor.authorStubbs, K.A.
dc.contributor.authorMylne, J.S.
dc.date.issued2025
dc.description.abstractModern 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.
dc.description.statementofresponsibilityJoel 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
dc.identifier.citationMolecular Plant, 2025; 18(8):1294-1309
dc.identifier.doi10.1016/j.molp.2025.06.016
dc.identifier.issn1674-2052
dc.identifier.issn1752-9867
dc.identifier.orcidMcDougal, D.P. [0000-0003-4499-6789]
dc.identifier.orcidBruning, J.B. [0000-0002-6919-1824]
dc.identifier.urihttps://hdl.handle.net/2440/147711
dc.language.isoen
dc.publisherOxford University Press (OUP)
dc.relation.granthttp://purl.org/au-research/grants/arc/DP190101048
dc.relation.granthttp://purl.org/au-research/grants/arc/DE180101445
dc.relation.granthttp://purl.org/au-research/grants/arc/LE230100156
dc.rights© 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.
dc.source.urihttps://doi.org/10.1016/j.molp.2025.06.016
dc.subjectherbicide; dihydrofolate reductase; thymidylate synthase; protein structure
dc.subject.meshHumans
dc.subject.meshArabidopsis
dc.subject.meshTetrahydrofolate Dehydrogenase
dc.subject.meshThymidylate Synthase
dc.subject.meshArabidopsis Proteins
dc.subject.meshHerbicides
dc.subject.meshModels, Molecular
dc.titleStructural insights into a plant-conserved DHFR-TS reveal a selective herbicide target
dc.typeJournal article
pubs.publication-statusPublished

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