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.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-09
DOI
https://doi.org/10.64898/2026.11.06.764869
Primary Topic
Receptor Mechanisms and Signaling
Type
preprint
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preprint

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

Scott C. Blanchard, Sukanta Bar, Joshua B. Kelley, Adelaine Kwun-Wai Leung et al.
bioRxiv (Cold Spring Harbor Laboratory)
Receptor Mechanisms and Signaling
preprint

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

Scott C. Blanchard, Sukanta Bar, Joshua B. Kelley, Adelaine Kwun-Wai Leung, Stephen H. McLaughlin, Wesley B. Asher, Henrik Gunnar Dohlman, Nagarajan Vaidehi, Jonathan A. Javitch, Vaithish Velazhahan, Ning Ma, Christopher G. Tate, Qingchao Chen, Sudati Shrestha, Yue Ren, Manning Jamie, Maxwell Martin, Henry Dalton Taylor
preprint en

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.

bioRxiv (Cold Spring Harbor Laboratory)
University of North Carolina at Chapel Hill (US), St. Jude Children's Research Hospital (US), MRC Laboratory of Molecular Biology (GB), University of Saskatchewan (CA), Beckman Research Institute (US), New York State Psychiatric Institute (US), Columbia University (US), University of Maine (US), Stanford University (US)
Receptor Mechanisms and Signaling
DOIOpen Access PDFOpenAlex
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