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      SP-141 targets Trs85 to inhibit rice blast fungus infection and functions as a potential broad-spectrum antifungal agent

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          Abstract

          Rice blast is a devastating disease worldwide, threatening rice production and food security. The blast fungus Magnaporthe oryzae invades the host via the appressorium, a specialized pressure-generating structure that generates enormous turgor pressure to penetrate the host cuticle. However, owing to ongoing evolution of fungicide resistance, it is vitally important to identify new targets and fungicides. Here, we show that Trs85, a subunit of the transport protein particle III complex, is essential for appressorium-mediated infection in M. oryzae. We explain how Trs85 regulates autophagy through Ypt1 (a small guanosine triphosphatase protein) in M. oryzae. We then identify a key conserved amphipathic α helix within Trs85 that is associated with pathogenicity of M. oryzae. Through computer-aided screening, we identify a lead compound, SP-141, that affects autophagy and the Trs85–Ypt1 interaction. SP-141 demonstrates a substantial capacity to effectively inhibit infection caused by the rice blast fungus while also exhibiting wide-ranging potential as an antifungal agent with broad-spectrum activity. Taken together, our data show that Trs85 is a potential new target and that SP-141 has potential for the control of rice blast. Our findings thus provide a novel strategy that may help in the fight against rice blast.

          Abstract

          This study reveals the mechanism by which the Trs85–Ypt1 module regulates autophagy in M. oryzae. Based on the structure of Trs85, a lead antifungal compound, SP-141, has been identified through virtual screening. This inhibitor affects autophagy and shows great potential for control of rice blast.

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          Most cited references44

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          Autophagy: renovation of cells and tissues.

          Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy's role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments.

            Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.
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              Autophagy regulates lipid metabolism.

              The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
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                Author and article information

                Contributors
                Journal
                Plant Commun
                Plant Commun
                Plant Communications
                Elsevier
                2590-3462
                27 September 2023
                12 February 2024
                27 September 2023
                : 5
                : 2
                : 100724
                Affiliations
                [1 ]State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Biotechnology, Zhejiang University, Hangzhou 310058, Zhejiang Province, China
                [2 ]State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou 310058, Zhejiang Province, China
                [3 ]Department of Pharmacology and Nutritional Science, College of Medicine, The University of Kentucky, Lexington, KY 40506, USA
                [4 ]Markey Cancer Center, College of Medicine, The University of Kentucky, Lexington, KY 40506, USA
                [5 ]College of Life Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China
                [6 ]Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects, Zhejiang University, Hangzhou 310058, Zhejiang Province, China
                [7 ]Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Shanghai 201106, Shanghai, China
                Author notes
                []Corresponding author fuchenglin@ 123456zju.edu.cn
                [∗∗ ]Corresponding author xhliu@ 123456zju.edu.cn
                [8]

                These authors contributed equally to this article.

                Article
                S2590-3462(23)00270-5 100724
                10.1016/j.xplc.2023.100724
                10873891
                37771153
                001a0d03-ae33-4399-98d6-edbea5b660fe
                © 2023 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 5 May 2023
                : 12 June 2023
                : 25 September 2023
                Categories
                Research Article

                magnaporthe oryzae,rice blast,trappiii complex,trs85,fungicide

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