Biology subjects

Adamczyk, J.

Publications and source records attributed to Adamczyk, J..

2 recordsLinked to original sources

bioRxiv2025

Exploration of chemical probes and conformational flexibility of GID4 - the substrate receptor of human CTLH E3 ligase complex

The application of targeted protein degradation (TPD) is currently constrained by the limited availability of low-molecular-weight molecules that can recruit E3 ligases other than CRBN (Cereblon) or VHL (Von Hippel-Lindau ligase). In this study, we present the structure-based drug design (SBDD) of high-affinity ligands that engage E3 ligase GID4 (Glucose-induced degradation protein 4) in biophysical and cellular experiments. Through structural studies and molecular modeling, we identified three clusters of compounds that induce distinct conformations of GID4. We characterized potential exit vectors and used the most promising ligand as a building block to prepare bifunctional degraders in the form of proteolysis-targeting chimeras (PROTACs). Although ternary complex formation was successful in vitro, degradation of BRD4 was not observed, highlighting the need for further optimization of the degraders. Finally, we theoretically investigated the likelihood of the identified GID4 conformations participating in protein-protein interactions mediated by molecular glue mechanisms. We believe the expanded ligand diversity discovered in this study may pave the way for tuning the selectivity and efficacy of interactions involving GID4 and its neosubstrates. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/662521v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@19187e8org.highwire.dtl.DTLVardef@171abd1org.highwire.dtl.DTLVardef@1c75a5forg.highwire.dtl.DTLVardef@fe17fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Honey bee Apis mellifera L. Responses to Oxidative Stress Induced by Pharmacological and Pesticide Compounds

The western honey bee, Apis mellifera L., is a eusocial insect that plays major roles in ecosystem balances and pollination of plants and food crops. Honey bees face multiple biotic and abiotic stressors, such as pathogens, diseases, chemical pesticides, and climate change, which all contribute to honey bee colony loss. This study investigated the impacts of multiple pharmacological and pesticide molecules on honey bee survival and gene regulation responses. In an 11-day cage experiment, sublethal doses of tunicamycin, thapsigargin, metformin, paraquat, hydrogen peroxide, and imidacloprid were administered to newly emerged sister bees. Daily treatment consumption and mortality were recorded, as well as the transcription expression of twelve major genes (AChE-2, Apisimin, Apidaecin, mrjp1, Sodq, cp450, SelT, SelK, Ire1, Xbp1, Derl-1, Hsc70), some of which are markers of oxidative and endoplasmic reticulum (ER) stresses in honey bees. At day 9 of the treatments, protein damage was quantified in caged bees. Kaplan-Meier model indicated significant (p < 0.001) toxicological effects of paraquat, H2O2 and tunicamycin on bee survivorship compared to controls with better survivals for other molecules. Post-ingestive aversion responses were recorded only in the case of tunicamycin, hydrogen peroxide and imidacloprid. Nonetheless, significantly higher protein damage on day 9 was only identified in bees exposed to paraquat and imidacloprid. Some antioxidant genes significantly regulated vis-a-vis specific treatments. Our results reveal age-related regulation of other major genes with significant inter-gene positive correlations.

zoology↗