Sulfur-containing amino acids in 7TMRs: molecular gears for pharmacology and function

• 7TMRs contain a large number of sulfur–sulfur and sulfur–aromatic interactions.
• Met and Cys residues of 7TMRs govern important signaling and functional events.
• Met–arene interactions stabilize 7TMR states related to specific signaling pathways.
• Met–arene interactions tune the orientation of functional aromatic residues.

Seven-transmembrane receptors (7TMRs) mediate the majority of physiological responses to hormones and neurotransmitters in higher organisms. Tertiary structure stability and activation of these versatile membrane proteins require formation or disruption of complex networks of well-recognized interactions (such as H-bonds, ionic, or aromatic–aromatic) but also of other type of interactions which have been less studied. In this review, we compile evidence from crystal structure, biophysical, and site-directed mutagenesis data that indicate or support the importance of interactions involving Met and Cys in 7TMRs in terms of pharmacology and function. We show examples of Met/Cys–aromatic and Met–Met interactions participating in ligand binding, in tuning the orientation of functionally important aromatic residues during activation or even in modulating the type of signaling response. Collectively, data presented enlarge the repertoire of interactions governing 7TMR functioning.