Structure-based virtual screening identifies small-molecule inhibitors of O-fucosyltransferase SPINDLY in Arabidopsis

• DOI: 10.1093/plcell/koad299
• Publication Date: 2023-12-21T06:31:23Z
• Authors: Yalikunjiang Aizezi; Hongming Zhao; Zhenzhen Zhang; Yang Bi; Qiuhua Yang; Guangshuo Guo; Hongliang Zhang; Hongwei Guo; Kai Jiang; Zhi-Yong Wang
• Keywords: Fucosyltransferase

Protein O-glycosylation is a nutrient signaling mechanism that plays an essential role in maintaining cellular homeostasis across different species. In plants, SPINDLY (SPY) and SECRET AGENT (SEC) posttranslationally modify hundreds of intracellular proteins with O-fucose O-linked N-acetylglucosamine, respectively. SPY SEC play overlapping roles regulation, loss both causes embryo lethality Arabidopsis (Arabidopsis thaliana). Using structure-based virtual screening chemical libraries followed by vitro planta assays, we identified O-fucosyltransferase inhibitor (SOFTI). Computational analyses predicted SOFTI binds to the GDP-fucose-binding pocket competitively inhibits GDP-fucose binding. assays confirmed interacts its activity. Docking analysis additional analogs showed stronger inhibitory activities. treatment seedlings decreased protein O-fucosylation elicited phenotypes similar spy mutants, including early seed germination, increased root hair density, defective sugar-dependent growth. contrast, did not visibly affect mutant. Similarly, inhibited growth tomato (Solanum lycopersicum) seedlings. These results demonstrate specific can be used as tool for functional studies potentially agricultural management.