The D816V activating mutation of the c-Kit kinase domain often causes human mastocytosis. Although inhibitors of wild-type c-Kit are known (e.g. STI-571), they are at least 10 times less active against the c-Kit mutant. Several derivatives of ellipticine (5,11-dimethyl-6H-pyrido[3,4-b]carbazole), substituted at positions 1, 2, 9, and 11, were found to inhibit purified D816V and wild-type c-Kit kinase domains with comparable potencies by competing with ATP binding. We investigated the difference between these inhibitors by modeling the D816V mutation in crystal structures of inactive and active c-Kit. Molecular dynamics simulations strongly suggested that the D816V point mutation shifts the conformational equilibrium of c-Kit kinase domain toward the active conformation. All ellipticine compounds were subsequently docked to the D816V mutant c-Kit model. The model provides possible explanations for the structure-activity relationships observed among ellipticine compounds, resulting in new insights into D816V c-Kit mutant inhibition.
Pleiotropic effects are one of the main concerns regarding genetically modified organisms (GMOs). This includes unintended side effects of the transgene or its genome insertion site on the regulation of other endogenous genes, which could potentially cause the accumulation of different secondary metabolites that may have not only an impact on diet as repeatedly worried by the public but also on the environment. Regarding amount and possible environmental effects, flavonoids represent the most prominent group of secondary metabolites in wheat. Many flavonoids function as signalling or defence molecules. We used a robust and reproducible analytical method to compare the flavonoid content of genetically modified (GM) wheat (Triticum aestivum L., Gramineae) expressing genes that confer increased fungal resistance with their non-GM siblings. The transgenes provide either a broad-spectrum fungal defence (chitinase/glucanase from barley) or bunt-specific resistance by a viral gene (KP4). Significant differences in flavonoid composition were found between different wheat varieties whereas different lines of GM wheat with increased antifungal resistance showed only minor differences in their flavonoid composition relative to their non-GM siblings. In a field test, no significant differences were detectable between infected and non-infected wheat of the same variety regardless of the presence of the transgene. Our results are in agreement with the hypothesis that the transgenes we used to increase wheat defence to fungal pathogens do not interfere with the flavonoid biosynthesis pathway. More significantly, the genetic background resulting from conventional breeding has a direct impact on the biological composition of flavonoids, and thus possibly on the environment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.