The SERT Na2 site is disrupted in the inward-open conformation. Aligned structures of SERT in outward-open (PDB accession no. 5I6X) and inward-open (PDB accession no. 6DZZ) conformations showing the movement of TM1a away from TM8 in the inward open conformation, which disrupts the Na2 site. Note the distances between the Na⁺ ion and the coordinating backbone carbonyl oxygen atoms of V97 and G94 in TM8, which increase from 2.4 Å and 2.5 Å, respectively, in the outward-open structure to 3.9 Å and 6.3 Å in the inward-open conformation.