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bioRxiv · 10.64898/2026.11.06.764869

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

Velazhahan, V.·Manning, J.·Ma, N.·Taylor, H. D.·Shrestha, S.·Chen, Q.·Ren, Y.·McLaughlin, S. H.·Leung, A.·Bar, S.·Martin, M.·Blanchard, S.·Asher, W. B.·Kelley, J. B.·Dohlman, H.·Vaidehi, N.·Javitch, J.·Tate, C. G.
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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.

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Velazhahan, V., Manning, J., Ma, N., Taylor, H. D., Shrestha, S., Chen, Q., Ren, Y., McLaughlin, S. H., Leung, A., Bar, S., Martin, M., Blanchard, S., Asher, W. B., Kelley, J. B., Dohlman, H., Vaidehi, N., Javitch, J., Tate, C. G.. 2026-11-09. Positive cooperativity enhances coupling of a second G protein to a GPCR dimer. https://doi.org/10.64898/2026.11.06.764869

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