Structural insights into promiscuous GPCR-G protein coupling

G protein-coupled receptors (GPCRs) transduce extracellular signals across biological membranes by activating heterotrimeric Gαβγ proteins. There are 16 different human Gα proteins grouped into four families (GS, Gi/O, Gq/11 and G12/13), each one activating different signaling cascades. Around 50% of non-olfactory GPCRs activate more than one type of Gα proteins with different efficacy and kinetics, triggering a fingerprint-like signaling profile. In this chapter we review the GPCR-G protein promiscuity landscape and discuss recent structures of GPCRs coupled to different Gα proteins. Overall, the size and shape of the intracellular cavity (determined by the extent of outward movement of TM6) is maintained when the receptor is coupled to different Gα proteins, and is determined by the type of primary Gα coupling. The "sub-optimal" secondary Gα coupling is further supported by interactions with the intracellular loops, with ICL2 and ICL3 having a relevant role in promiscuous couplings