Structural basis of heteromeric amino acid transporters and advances in targeted drug development

Heteromeric amino acid transporters (HATs), formed by the assembly of solute carrier 3(SLC3) and solute carrier 7(SLC7) family members, play essential roles in amino acid transmembrane transport, cellular nutrient sensing, and redox homeostasis. Dysregulation of multiple HATs members has been closely associated with tumor metabolic reprogramming, ferroptosis resistance, and inherited amino acid metabolic disorders, making them important targets for drug development. However, the high conservation of substrate-binding pockets, the limited druggability of zwitterionic compounds, and safety concerns arising from their broad expression in normal tissues have collectively hindered the clinical translation of HATs-targeted therapeutics. Recent advances in cryo-electron microscopy (Cryo-EM) have enabled the determination of high-resolution structures of multiple HATs, providing a critical foundation for understanding their molecular mechanisms and for guiding targeted interventions. These structural studies have systematically revealed the molecular basis of selective substrate recognition and ion coupling among different family members and have identified non-conserved structural features that may serve as potential opportunities for subtype-selective targeting. In this review, we systematically summarize recent advances in the structural biology of HATs, with a particular emphasis on their assembly mechanisms, substrate recognition modes, and conformational transitions. Furthermore, we highlight recent progress in structure-based drug design (SBDD), including strategies to enhance ligand affinity by exploiting non-conserved hydrophobic side pockets, as well as approaches to block the transport cycle by disrupting the secondary structures of transmembrane helices TM3 and TM10. Collectively, these insights provide an important structural framework and new perspectives for the development of highly selective inhibitors for HATs and related therapeutic strategies.