Figure 7

Applications for potential modes of T3 binding at MCT8 by comparison between the crystallized hormone/receptor complex and the structural MCT8 model. A) T3 is bound to its receptor in a specific mode characterized by several molecular interactions like H-bonds to a positively charged arginine and a histidine (figure 6A). The amino acid side chains are in a certain distance to each other in a range between 14.4 and 15.3 Å. B) Measurement of the distances between the histidines and positively charges residues in the MCT8 model (“inside-open” conformation) reveals three combinations of Arg-His pairings in a similar distance to each other (red translucent regions V1-V3 (V–variant)). Although the distance between R445 (highly conserved among the MCTs) and H192 is around 15 Å, some hydrophilic amino acids are in close spatial distance (V1) which would cause sterical clashes with the T3 substrate. In another transporter conformation this might be different. Of note, R445 and H192 are functionally important as demonstrated by pathogenic mutations (figure 3A). The importance of R445 for transport was also shown by directed mutagenesis.