Deciphering the ligand/xenobiotic molecular recognition mechanism in SLC transporters via a new structural binding site analysis

The Solute Carrier (SLC) superfamily of transporters is the second largest group of transmembrane proteins, only second to GPCRs [1]. Overall, they are able to transport a wide variety of solutes across membranes, from sugars, to nucleotides, to amino acids, to exogenous compounds, such as drugs. Despite being ubiquitous and playing many important roles in human physiology and disease, there is still much to learn about the structure and function of these proteins [2]. Their heterogeneity in both function and overall folding is one of the main factors that complicate their study and classification. More than 400 SLCs are currently known, divided into 66 subfamilies according to amino acid sequence similarity. Attempts to further group these subfamilies have been made according to different parameters such as their folding, but none were actually able to fully overcome their heterogeneity and classify them all [3]. Additionally, even inside of the same subfamily, individual members are differently selective for the transported solutes. In this work, we used a novel computational 3D approach [4] for the analysis of the binding sites to get potentially useful information to further our understanding of the SLCs recognition mechanism, to help in their classification, and to choose the best template to perform homology modelling of transporters whenever an experimentally solved structure is not available. Interesting insights have emerged on the relationship between primary structures and recognition sites from the analysis of a relatively small SLC database. Further in-depth analyses of larger SLC databases are in progress to confirm such preliminary and promising results.