PT  - JOURNAL ARTICLE
AU  - Joel Haywood
AU  - Karen J. Breese
AU  - Jingjing Zhang
AU  - Mark T. Waters
AU  - Charles S. Bond
AU  - Keith A. Stubbs
AU  - Joshua S. Mylne
TI  - A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action
AID  - 10.1101/2022.04.18.488698
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.18.488698
4099  - http://biorxiv.org/content/early/2022/08/02/2022.04.18.488698.short
4100  - http://biorxiv.org/content/early/2022/08/02/2022.04.18.488698.full
AB  - Decades of intense herbicide use has led to resistance in weeds. Without innovative weed management practices and new herbicidal modes of action, the unabated rise of herbicide resistance will undoubtedly place further stress upon food security. HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. As HMGR inhibitors have been shown to be herbicidal, HMGR could represent a new mode of action target for the development of herbicides. Here we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) which exhibits a wider active site than previously determined structures from different species. This plant conserved feature enabled the rational design of specific HMGR inhibitors, for which we engineered a tolerance trait through sequence analysis of fungal gene clusters. These results suggest HMGR to be a viable herbicide target modifiable to provide a tolerance trait.Competing Interest StatementThe authors have declared no competing interest.