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

Year: 2026
Type: preprint
Abstract: 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.
DOI: 10.64898/2026.11.06.764869
Authors: Vaithish Velazhahan, Jamie Manning, Ning Ma, Henry Dalton Taylor, Sudati Shrestha, Qingchao Chen, Yue Ren, Stephen H McLaughlin, Adelaine Leung, Sukanta Bar, Maxwell Martin, Scott Blanchard, Wesley B. Asher, Joshua B Kelley, Henrik Dohlman, Nagarajan Vaidehi, Jonathan Javitch, Christopher G Tate
Institutions: Stanford University, Columbia University, Beckman Research Institute, University of North Carolina at Chapel Hill, University of Maine, MRC Laboratory of Molecular Biology, University of Saskatchewan, St. Jude Children's Research Hospital, New York State Psychiatric Institute
Language: English
Open Access status: green
OpenAlex ID: W7225646056
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