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Structure-based virtual screening identifies small molecule inhibitors of O-fucosyltransferase SPINDLY
Open accessPreprint — published as 10.1093/plcell/koad299 · Paper page
Abstract
Protein O-glycosylation is a nutrient-signaling mechanism that plays essential roles in maintaining cellular homeostasis across different species. In plants, SPINDLY (SPY) and SECRET AGENT (SEC) catalyze posttranslational modifications of hundreds of intracellular proteins by O-fucose and O-linked N-acetylglucosamine, respectively. SPY and SEC play overlapping roles in cellular regulation and loss of both SPY and SEC causes embryo lethality in Arabidopsis. Using structure-based virtual screening of chemical libraries followed by in vitro and in planta assays, we identified a S PY O - f ucosyltransferase i nhibitor (SOFTI). Computational analyses predicted that SOFTI binds to the GDP-fucose-binding pocket of SPY and competitively inhibits GDP-fucose binding. In vitro assays confirmed that SOFTI interacts with SPY and inhibits its O-fucosyltransferase activity. Docking analysis identified additional SOFTI analogs that showed stronger inhibitory activities. SOFTI treatment of Arabidopsis seedlings decreased protein O-fucosylation and caused phenotypes similar to the spy mutants, including early seed germination, increased root hair density, and defect in sugar-dependent growth. By contrast, SOFTI had no visible effect on the spy mutant. Similarly, SOFTI inhibited sugar-dependent growth of tomato seedlings. These results demonstrate that SOFTI is a specific SPY O-fucosyltransferase inhibitor and a useful chemical tool for functional studies of O-fucosylation and potentially for agricultural management.
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Metadata
- Authors
- Aizezi, Y., Zhao, H., Zhang, Z., Bi, Y., Yang, Q., Guo, G., Zhang, H., Guo, H., Jiang, K., & Wang, Z.-Y.
- Affiliations
- Carnegie Institution for Science (US)
- Southern University of Science and Technology (CN)
- Corresponding author
- Jiang, Kai
- ORCID
- Venue
- The Plant Cell
- Publisher
- openRxiv
- Published
- 2023-06-14
- Volume
- 36
- Issue
- 3
- Pages
- 497-509
- ISSN
- 1040-4651 (ISSN-L)
- PMC
- PMC10896289
- OpenAlex
- W4390055243
- Cited by
- 16
- References
- 1
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- The Plant Cell (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Natural Science Foundation of China (21907049, 3191154007091740203)
- National Institutes of Health
- University of California, Davis
- National Institute of General Medical Sciences (R01GM066258)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Polysaccharides and Plant Cell Walls
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- SPINDLY, O-fucosylation, O-glycosylation, small molecule inhibitors, structure-based virtual screening, spies, Arabidopsis thaliana, tomato, root hair density, seed germination, nutrient signaling
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