To achieve this goal, the REsolution project compiled information on the entire class of SLCs, creating a central database to assess their association with human diseases. Next, REsolution selected several SLCs involved in disease for experimental studies. Through the generation of biological tools, deep mutational scanning (DMS) datasets, transport assays, and experimental characterization of disease-related variants, REsolution provided a key toolkit for future drug discovery for these targets.
Our key achievements include:
• Over 200 plasmids and cell lines were generated for SLC genetic variants involved in human diseases. These reagents enabled the molecular characterization of disease mutants.
• Deep mutational scanning (DMS) datasets were acquired for SLC13A5, SLC19A1, and SLC2A1, providing valuable insights into the impact of all possible genetic variation in respective SLCs (manuscripts in preparation).
• Transport assays were developed to assess disease-related variants of various SLCs. This enabled the investigation of whether and how disease mutants impact the SLC’s transport function.
• Experimental characterization of SLC single variants for several targets (SLC6A8 published in Ferrada et al., J Mol Biol, 2024; SLC1A3 published in Gorostiola González, M., Sijben, H., et al., Front. Mol. Biosci., 2023 and several manuscripts in preparation). These studies provide in-depth analyses of disease mutants and contribute to a better understanding of respective diseases.
• A structural analysis on the entire SLC family of transporters was performed using experimental, homology and AlphaFold2 predictions-based structural databases (Ferrada & Superti-Furga iScience 2022). This improves our understanding of structural similarity between SLCs and supports the interpretation of genetic variation.
The project's results are disseminated through the SLC Knowledgebase (
https://re-solute.eu/knowledgebase(odnośnik otworzy się w nowym oknie)) as well as a web portal (
https://re-solute.eu/resolution(odnośnik otworzy się w nowym oknie)) offering interactive tools like the genetic scoreboard, compendium, and phenotypes dashboards. Scientific publications, conference presentations, and workshops, including those during the Final RESOLUTE conference “Unlocking Transporter for Drug Discovery” (talks available at
https://re-solute.eu/conference(odnośnik otworzy się w nowym oknie)) amplified the global visibility of SLCs in human diseases. In general, the project's commitment to open-access and knowledge dissemination, evident through the mentioned resources and activities, ensured that the broader scientific and medical communities are equipped with the latest insights. This collaborative approach fosters a collective understanding of SLCs' significance in human diseases and may catalyze further research on this class of proteins.
