Sodium-dependent membrane transporters of the SLC6 family mediate the transport of amino acids and monoamines. Their neural representatives, such as B⁰AT2 (SLC6A15), NTT4 (SLC6A17), and SIT1 (SLC6A20), transport neutral amino acids and thereby maintain glutaminergic homeostasis by supplying neurons and glial cells with precursors for the glutamine-glutamate-GABA cycle. Their dysfunction has been associated with anxiety, mental retardation, or NMDA receptor hypofunction ¹. The structures of these transporters are poorly understood and remain an area of research. In doing so, we carried out computational investigations followed by cryo-EM and kinetic studies. As a result, we have collected data that advance our understanding of the structure, membrane anchoring, mechanism of substrate transport and inhibition. Fine feedback, with the discovery of first-in-class potent inhibitors of B⁰AT2 and SIT1, has validated our computational methods. Our findings will guide further structural studies toward a mechanistic understanding of transporter function.  Furthermore, the discovery of new inhibitors will also be an aid in the design of another. Such a compounds will be useful for investigating the therapeutic relevance of their targets as well as for deciphering the physiology of the glutaminergic system.