Figure 4.

Unlike rhodopsin, a tryptophan at position 6.48 of TMH6 is not tolerated in the TSHR. A) Superimposition of the TSHR homology model (red residues) in the basal state with particular residues of the structural template (inactive bovine rhodopsin) are shown (pale beige residues). In the TSHR, M637 is located at the same position (6.48) as W265 in rhodopsin. Residues interacting with the bulky tryptophan (6.48) of rhodopsin are the small alanine and serine at positions 7.42 and 7.45 in TMH7, whereas those interacting with methionine (6.48) (which is smaller than tryptophan) of the TSHR in the basal conformation are larger residues, tyrosine and asparagine, at positions 7.42 and 7.45. Introduction of a tryptophan at position 6.48 in the TSHR basal state model causes a clash and thus repulsion with the large Y7.42 side chain in TMH7. B) TSHR model (orange) of the active state based on the structure of opsin is shown with the allosteric ligand binding pocket of wt TSHR. In addition to residue M637, superimpositions of the mutations M637W and M637C are shown at position 6.48. The bulkier tryptophan side chain (red) clearly extends into the allosteric binding pocket (yellow) and causes steric hindrance (red arrow) of the agonist c2 (blue)/TSHR interaction, whereas the smaller cysteine side chain (green) does not influence the ligand binding site similar to wt methionine (yellow).