The role of G protein conformation in receptor-G protein selectivity

G protein-coupled receptors (GPCRs) selectively activate at least one of the four families of heterotrimeric G proteins, but the mechanism of coupling selectivity remains unclear. Structural studies emphasize structural complementarity of GPCRs and nucleotide-free G proteins, but selectivity is likely to be determined by transient intermediate-state complexes that exist before nucleotide release. Here we study coupling to nucleotide-decoupled G protein variants that can adopt conformations similar to receptor-bound G proteins without releasing nucleotide, and are therefore able to bypass intermediate-state complexes. We find that selectivity is degraded when nucleotide release is not required for GPCR-G protein complex formation, to the extent that most GPCRs interact with most nucleotide-decoupled G proteins. These findings demonstrate the absence of absolute structural incompatibility between noncognate receptor-G protein pairs, and are consistent with the hypothesis that transient intermediate states are partly responsible for coupling selectivity.

Automated summary

By studying G protein variants that can form GPCR-G protein complexes without nucleotide release, it was found that selectivity is reduced and most GPCRs interact with most variants. These findings suggest the absence of absolute structural incompatibility between noncognate receptor-G protein pairs and support the role of transient intermediate states in coupling selectivity.