Key for a lock: using structural biology in new mode-of-action herbicide development

Title:  Key for a lock: using structural biology in new mode-of-action herbicide development

Speaker: Professor Josh Mylne of Curtin University

Abstract:  Herbicide discovery was in its heyday between 1952 and 1984 with a new herbicide mode of action coming to market every other year. Since then however a number of factors have stymied development and only one new mode-of-action has come to market. Many weeds now have evolved to survive the existing modes-of-action and in some cases, superweeds are able to resist herbicides from up to eight different modes-of-action. After this long hiatus, crop protection companies have begun increasing their R&D efforts to discover new modes-of-action. Many of the approaches are being borrowed from the pharmaceutical industry. One approach to ensure a new mode-of-action is to employ a target-first, structural biology approach where the 3D structure of the novel target protein is used to either rationally improve herbicidal molecules, or even be used to design completely new herbicidal molecule ab initio with cheminformatics guiding choices [1]. Here I will describe our progress after solving crystal structures of three herbicide target proteins, one a known target [2] and two that represent potential new herbicide targets [3].

[1] Pires, Stubbs, Mylne, Ascher (2022) cropCSM: designing safe and potent herbicides with graph-based signatures. Briefings in Bioinformatics 23: bbac042
[2] Vadlamani, Sukhoverkov, Haywood, Breese, Fisher, Stubbs, Bond, Mylne (2022) Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam. Plant Communications 3: e100322.
[3] Haywood, Breese, Zhang, Waters, Bond, Stubbs, Mylne (2022) A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action. Nature Communications 13: 5563

Biography: Josh is a geneticist and biochemist who has worked broadly in plant genetic engineering (PhD Botany, UQ 2002), developmental genetics and epigenetics at the UK’s John Innes Centre (2001-2005) and peptide biochemistry at UQ’s IMB (2006-2012). He held successive, Australian Research Council QEII and Future Fellowships (2008-2016), was Australia’s 2012 Goldacre Medal winner, a 2014 Feinberg Foundation Visiting Fellow to the Weizmann in Israel and spent a winter at the University of Minnesota as a 2018 Fulbright Professional Scholar. He founded his lab in Perth at the UWA School of Molecular Sciences (mylne.org) in 2013, became tenured in 2017 and an Associate Professor in 2018. In 2021 he became a Professor and the Deputy Director at Curtin University's Centre for Crop and Disease Research. His lab has focussed on studies in protein evolution, peptide biosynthesis and structural enzymology, but currently pursues (a) herbicide development and target protein biochemistry and (b) fungicide metabolism in crops using mass spectrometry.