Fig. 2: Alternating access enables metformin translocation.
From: Structural insights into human organic cation transporter 1 transport and inhibition
a A sliced view of the hOCT1 in the outward open (hOCT1-M1), outward occluded (hOCT1-M2), inward occluded (hOCT1-M3), and inward open (hOCT1-apo1) conformations. Metformin binds to the central pocket of hOCT1 in different states. The surface of the hOCT1 is colored according to the electrostatic potential calculated by ChimeraX. b Structural comparison of the outward open (hOCT1-M1) (orange) and outward occluded (hOCT1-M2) (green) conformations. The extracellular ends of transmembrane helices in the CTD (black dashed box) exhibit conformational rearrangement. c Structural comparison of the metformin binding pockets in the outward open (hOCT1-M1) (orange) and outward occluded (hOCT1-M2) (green) conformations. Compared to the outward open conformation, metformin moves slightly towards the NTD in the outward occluded conformation. A red double arrow shows the cation-π interaction between Y361 and metformin. d Structural comparison of the outward occluded (hOCT1-M2) (green) and inward occluded (hOCT1-M3) (cyan) conformations. The transmembrane helices in the CTD (black dashed box) exhibit conformational rearrangements. The red dashed box highlights the extracellular end of TM7 that rearranges from a loop to a helix during conformational change. e Structural comparison of the metformin binding pockets in outward occluded (hOCT1-M2) (green) and inward occluded (hOCT1-M3) (cyan) conformations. Metformin moves to a deeper position in the inward occluded conformation. f Structural comparison of the inward occluded (hOCT1-M3) (cyan) and inward open (hOCT1-apo1) (magenta) conformations. The intracellular ends of transmembrane helices in the CTD (black dashed box) exhibit conformational rearrangement. g Structural comparison of the metformin binding pockets in inward occluded (hOCT1-M3) (cyan) and inward open (hOCT1-apo1) (magenta) conformations. h Mutating the residues at the metformin binding pocket resulted in varied effects on the uptake activity of metformin (green) and MPP+ (orange). Data are normalized to wild-type hOCT1 and are given as mean ± SEM of four independent samples. i During the metformin translocation cycle, the CTD of hOCT1 undergoes notable conformational rearrangement. The residues Y361 and W354 play key roles in the process.
