Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters—Example of the SLC6 and SLC7 Families

Abstract

SLC transporters are emerging key drug targets. One important step for drug development is the profound understanding of the structural determinants defining the substrate selectivity of each transporter. Recently, the improvement of computational power and experimental methods such as X-ray and cryo-EM crystallography permitted to conduct structure-based studies on specific transporters having important pharmacological impact. However, a lot remains to be discovered regarding their dynamics, transport modulation and ligand recognition. A detailed functional characterization of transporters would provide opportunities to develop new compounds targeting these key drug targets. Here, we are giving an overview of two major human LeuT-fold families, SLC6 and SLC7, with an emphasis on the most relevant members of each family for drug development. We gather the most recent understanding on the structural determinants of selectivity within and across the two families. We then use this information to discuss the benefits of a more generalized structural and functional annotation of the LeuT fold and the implications of such mapping for drug discovery.

Probing binding and occlusion of substrate in the human creatine transporter‐1 by computation and mutagenesis

“…We validated the model using molecular dynamics simulations and probed the ionization states of key titratable residues through experiment and computation. From this, we show that D458 is present in an uncharged state in CRT1, and contrary to previous proposals (Colas, 2020 ; Colas et al, 2020 ; Colas & Laine, 2021 ; Dodd & Christie, 2001 ; Stary & Bajda, 2023 ), C144 is not present in a charged state in the substrate binding site. Using this homology model as a starting point, we then docked creatine, the cognate substrate of CRT1, into the binding site.…”

Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1

“…Furthermore, we have to acknowledge limited predictive power of the used BGT1 homology model in the extracellular vestibule due to a one amino acid insertion in the middle of transmembrane 10. This insertion, which is located right between the interface of the orthosteric site and the extracellular vestibule, is a unique feature of the GATs (mouse, human, rat) and it is not observed in any of the other related SLC6 (e.g., monoamine transporters) transporters or related bacterial homologs (Beuming et al, 2006;Kickinger et al, 2019;Colas, 2020). Even though an extended conformation such as a π-helix was suggested for this insertion (Dayan et al, 2017), and an extended conformation is also present in the used homology model, the correct architecture of this feature will be only known upon the release of a BGT1 3D-structure.…”

The macrocycle inhibitor landscape of SLC‐transporter

“…The MAT subgroup consists of three prominent transporters: SLC6A2 (norepinephrine transporter, NET), SLC6A3 (dopamine transporter, DAT), and SLC6A4 (serotonin transporter, SERT). These transporters have garnered interest due to their involvement in modulating various signaling pathways in the brain, rendering them compelling and important drug targets [43,44]. The SLC6 (Neurotransmitter transporter family) inhibitors (depicted in the cornflower blue cluster) fall into two well-discriminated groups (Figure 5c), along with one singleton molecule (Figure 5d).…”