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PreprintCC BYbioRxiv

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

  • V. Velazhahan
  • J. Manning
  • N. Ma
  • H. D. Taylor
  • S. Shrestha
  • Q. Chen
  • Y. Ren
  • S. H. McLaughlin
  • A. Leung
  • S. Bar
  • M. Martin
  • S. Blanchard
6 more authors
  • W. B. Asher
  • J. B. Kelley
  • H. Dohlman
  • N. Vaidehi
  • J. Javitch
  • C. G. Tate1
  1. 1MRC LMB Cambridge, UK
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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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Cite

BibTeXRIS
BibTeX
@misc{velazhahan2026positive,
  title = {{Positive cooperativity enhances coupling of a second G protein to a GPCR dimer}},
  author = {V. Velazhahan and J. Manning and N. Ma and H. D. Taylor and S. Shrestha and Q. Chen and Y. Ren and S. H. McLaughlin and A. Leung and S. Bar and M. Martin and S. Blanchard and W. B. Asher and J. B. Kelley and H. Dohlman and N. Vaidehi and J. Javitch and C. G. Tate},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.06.764869},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764869v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Positive cooperativity enhances coupling of a second G protein to a GPCR dimer
AU  - V. Velazhahan
AU  - J. Manning
AU  - N. Ma
AU  - H. D. Taylor
AU  - S. Shrestha
AU  - Q. Chen
AU  - Y. Ren
AU  - S. H. McLaughlin
AU  - A. Leung
AU  - S. Bar
AU  - M. Martin
AU  - S. Blanchard
AU  - W. B. Asher
AU  - J. B. Kelley
AU  - H. Dohlman
AU  - N. Vaidehi
AU  - J. Javitch
AU  - C. G. Tate
PY  - 2026
DA  - 2026/11/06
PB  - bioRxiv
DO  - 10.64898/2026.11.06.764869
UR  - https://www.biorxiv.org/content/10.64898/2026.11.06.764869v1
AB  - 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.
ER  -