Crystal structure of Fatty Acid Thioesterase A bound by 129 fragments provides diverse development opportunities DOI Open Access
Eva Kot, Matteo P. Ferla,

Patricia H. Hollinshead

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

Abstract To alleviate the growing issue of herbicide resistance, diversification portfolio is necessary. A promising yet underutilised mode action (MoA) are Fatty Acid Thioesterases (Fat), which terminate de novo fatty acid (FA) biosynthesis by releasing acids from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility determining amount length FAs present. find novel chemical matter targeting this MoA we have solved crystal structure Arabidopsis thaliana FatA to 1.5Å conducted a crystallographic fragment screen identified 141 hits. Our fragments recapitulated interactions made current herbicides, but also targeted regions, namely active site dimer interface. Ten demonstrated on-scale potency, two those exploiting different known herbicides. The revealed large conformational changes exploited some fragments, including stabilisation loop shifts in ACP-binding lid domain. alter accessibility substrate binding reducing size apparent access channel. Finally, readily lend themselves designing compounds that both merge motifs allow catalogue-based SAR exploration. Elaboration one resulted an improvement affinity ∼20 μM ∼90nM KD. Thus our data may facilitate accelerated early discovery alternative inhibitors scaffolds modes interaction.

Language: Английский

Recent research highlights and innovations for sustainable crop protection DOI
Peter Maienfisch,

Karsten Koerber

Pest Management Science, Journal Year: 2025, Volume and Issue: 81(5), P. 2401 - 2405

Published: April 9, 2025

Abstract The global agricultural sector faces immense challenges in ensuring food security for a growing population while safeguarding environmental and human health. discovery of new products solutions the sustainable crop protection future is an imperative necessity matter great urgency. With purpose to showcase most recent innovations developments 15th IUPAC International Congress Crop Protection Chemistry was held 2023. This Special Issue comprises 26 articles provides information on latest research that were presented at this congress or resulted from accompanying discussions. © 2025 Society Chemical Industry.

Language: Английский

Citations

0
Crystal structure of Fatty Acid Thioesterase A bound by 129 fragments provides diverse development opportunities DOI Open Access
Eva Kot, Matteo P. Ferla,

Patricia H. Hollinshead

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

Abstract To alleviate the growing issue of herbicide resistance, diversification portfolio is necessary. A promising yet underutilised mode action (MoA) are Fatty Acid Thioesterases (Fat), which terminate de novo fatty acid (FA) biosynthesis by releasing acids from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility determining amount length FAs present. find novel chemical matter targeting this MoA we have solved crystal structure Arabidopsis thaliana FatA to 1.5Å conducted a crystallographic fragment screen identified 141 hits. Our fragments recapitulated interactions made current herbicides, but also targeted regions, namely active site dimer interface. Ten demonstrated on-scale potency, two those exploiting different known herbicides. The revealed large conformational changes exploited some fragments, including stabilisation loop shifts in ACP-binding lid domain. alter accessibility substrate binding reducing size apparent access channel. Finally, readily lend themselves designing compounds that both merge motifs allow catalogue-based SAR exploration. Elaboration one resulted an improvement affinity ∼20 μM ∼90nM KD. Thus our data may facilitate accelerated early discovery alternative inhibitors scaffolds modes interaction.

Language: Английский

Citations

0