Characterizing the Structure, Function, and Evolution of Human Solute Carrier (SLC) Transporters Using Computational Approaches

Abstract

Solute Carrier (SLC) transporters are membrane proteins that transport a broad range of solutes including metabolites, ions, toxins, and prescription drugs. In humans, there are about 400 SLC members, many of which are of medical importance. They can be drug target themselves (e.g., the serotonin transporter, SERT) or regulate the absorption, distribution, metabolism, and excretion (ADME) of drugs (e.g., the organic cation transporter 1, OCT-1). An important step toward describing the mechanisms of solute transport by SLC transporters includes computational or experimental characterization of their ligand-bound or unbound structures in different conformations. Due to a variety of technical issues, human SLC transporters are challenging targets for both experimental and computational characterizations. However, recent advances in computational approaches such as molecular docking and comparative modeling, coupled with the atomic structure determination of several membrane transporters, expanded our ability to characterize the human SLC families using in silico structure-based approaches. In this chapter, we first provide an overview of the structure, function, and pharmacology of the human SLC transporters. Second, we describe different computational methods, including sequence analysis, structural modeling, and ligand docking, that are commonly used, in combination with experimental testing, to characterize the human SLC transporters. Third, we demonstrate the utility of these approaches to characterize SLC members with three examples—the norepinephrine transporter (NET), the γ-aminobutyric acid (GABA) transporter 2 (GAT-2), and the l-type amino acid transporter (LAT-1). Finally, future directions in the field of computational structural biology of human SLC transporters are discussed.