Positive cooperativity enhances coupling of a second G protein to a GPCR dimer

G protein-coupled receptors (GPCRs) are cell surface integral membrane proteins that transduce environmental, hormonal and neurotransmitter molecular signals into intracellular responses. Here we studied a class D1 fungal receptor, Ste2, an obligate dimer that couples two G proteins per dimer and show that coupling of the second G protein has an 18-fold higher affinity than coupling of the first. The molecular mechanism uncovered suggests that coupling of the first G protein to one protomer stabilizes the adjacent protomer in an active conformation with a pre-formed G protein coupling site, thus increasing the affinity for coupling of the second G protein. Protomer-based stabilization of an adjacent protomer in a unique conformational state within a dimer may represent a general mechanism by which oligomerization alters GPCR pharmacology.