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.

Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma

“…The poly­(ethylene glycol) (PEG 400 , P) linker is used to covalently conjugate BG and TAT ligands. The reasoning behind the selection of the BG group was the similarity of the binding mechanism between BG and the NET system to the mechanism between the NET system and norepinephrine . The binding pocket of the NET system can interact with BG-P-TAT in several ways such as the aromatic ring of BG interacts with the hydrophobic moieties in the NET protein via van der Waals forces; positively charged guanidine of BG interacts with the carboxylate group of Asp75 of the NET protein binding site via ionic bonds; hydrogen bond interaction between BG and NET protein sites Ala145 and Phe72.…”

“…The reasoning behind the selection of the BG group was the similarity of the binding mechanism between BG and the NET system to the mechanism between the NET system and norepinephrine. 51 The binding pocket of the NET system can interact with BG-P-TAT in several ways such as the aromatic ring of BG interacts with the hydrophobic moieties in the NET protein via van der Waals forces; positively charged guanidine of BG interacts with the carboxylate group of Asp75 of the NET protein binding site via ionic bonds; hydrogen bond interaction between BG and NET protein sites Ala145 and Phe72. Other polar or π-electron interactions are also possible between the NET protein systems with ligands, but the small binding site of the NET pocket limits the size of binding ligands.…”

Proteochemometric Modeling Identifies Chemically Diverse Norepinephrine Transporter Inhibitors

“…Computational studies, such as statistical modeling and ligand docking, have increased in popularity over the past decades. However, application to SLCs has been relatively limited. , A 3D structure (crystal, cryo-EM, or homology-modeling based) of sufficient quality is required to perform structure-based drug discovery . However, the crystallization of SLCs is complex, given their membrane-bound nature, analogous to GPCRs.…”