A G protein-coupled receptor at work: the rhodopsin model

G protein-coupled receptors (GPCRs) are ubiquitous signal transducers in cell membranes, as well as important drug targets. Interaction with extracellular agonists turns the seven transmembrane helix (7TM) scaffold of a GPCR into a catalyst for GDP and GTP exchange in heterotrimeric Gαβγ proteins. Activation of the model GPCR, rhodopsin, is triggered by photoisomerization of its retinal ligand. From the augmentation of biochemical and biophysical studies by recent high-resolution 3D structures, its activation intermediates can now be interpreted as the stepwise engagement of protein domains. Rearrangement of TM5–TM6 opens a crevice at the cytoplasmic side of the receptor into which the C terminus of the Gα subunit can bind. The Gα C-terminal helix is used as a transmission rod to the nucleotide binding site. The mechanism relies on dynamic interactions between conserved residues and could therefore be common to other GPCRs.