Fig. 6: Transport cycle of LAT1 and inhibition mechanisms.
From: Structural basis of anticancer drug recognition and amino acid transport by LAT1
a–d Schematic representation of amino acid transport by LAT1 and its inhibition by JPH203 and BCH. All four panels represent experimental structures reported in the study. In the outward-facing state (a, b), LAT1 can accept substrates from extracellular solvent, with mobile Phe252 on TM6 facilitating access (b). The white transparent circle depicts the distal pocket predicted previously, and the yellow circle the hydrophobic space found in this study. When JPH203 binds (a), TM10 is bent, Phe252 closes, and TM1b and TM6a are pushed open, locking the transporter in the outward-facing state and blocking substrate access. Binding of BCH induces the occluded conformation (c), characterized by the rotation of Phe400 on TM10 toward the pocket. Eventually LAT1 transitions to the inward-facing state (d), which has low affinity for the substrate and releases it into the cell.
