Abstract
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. [Figure not available: see fulltext.].
Original language | English (US) |
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Pages (from-to) | 687-694 |
Number of pages | 8 |
Journal | Nature Chemical Biology |
Volume | 19 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2023 |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology