Molecular modeling of the orphan SLC6A16 transporter revealed an unusual composition of the substrate transport pathway

SLC6A16 (NTT5) is a poorly understood member of the solute carrier 6 (SLC6) family, a group of sodium-dependent transporters that shuttle amino acids and monoamines across cell membrane. While many SLC6 transporters have been well characterized, the substrate selectivity, and thereby the function of SLC6A16 remains unknown. Therefore, we employed computational modeling to predict the structures of human, bovine, and mouse variants of SLC6A16, which will guide future experimental studies on substrate selectivity. By comparing key features involved in transport and substrate recognition, we identified notable differences between SLC6A16 and other SLC6 family members, which typically share conserved elements. Moreover, our analyses suggest that human and bovine SLC6A16 might transport negatively charged amino acids such as glutamate and aspartate. Ultimately, our findings provide the first structural insights into SLC6A16 and offer testable hypotheses about its potential physiological role.