Asymmetric activation of class C GPCRs

Class C G-protein-coupled receptors (GPCRs) comprise a unique GPCR subfamily with large ligand-binding extracellular domains and function as obligate dimers. The recently resolved cryo-EM structures of full-length GABAB, CaSR, and mGlus have revealed that these receptors are activated in an asymmetric manner, leading to G-protein-coupling on one protomer within the receptor dimer. In this review we discuss the mechanisms of asymmetric activation in class C GPCRs and the unique mode of interaction with the inhibitory Gi protein. Upon activation, the two seven-transmembrane domains (7TMs) of class C GPCRs rearrange to form a conserved asymmetric TM6-TM6 interface. In contrast to class A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6, but is facilitated through the coordination of intracellular loops. Furthermore, positive and negative allosteric modulators (PAMs and NAMs) adopt distinct conformations to regulate the activity of class C GPCRs. Taken together, these recent findings on the mechanism of asymmetric activation of class C GPCRs highlight a novel mechanism of G protein activation and provide new insights into the design of therapeutics targeting these receptors.