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PreprintCC BY-NC-NDChemRxiv

Mature complexes carry more G protein class information than partner free GPCR structures

  • Hossein Batebi1,2
  1. 1Department of Physics
  2. 2Freie Universität Berlin
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Abstract

GPCR structures are widely used to infer G protein coupling and pathway selective pharmacology, but mature receptor G protein complexes may contain structural information acquired or stabilized after partner selection. We asked how much G protein class information is present independently of the bound transducer. We analyzed 1,360 experimental class A GPCR structures using structural bioinformatics, molecular recognition descriptors and receptor grouped machine learning. Every receptor with both a strict partner free active structure and a G protein bound structure entered the matched analysis; activation and evolutionary transfer served as controls. Twelve receptors met the strict criteria. Bound endpoints gave a larger G protein class margin in 11 of 12 receptors (mean difference 0.389, 95% CI 0.095 to 0.682; exact sign flip P = 0.030), with macro ROC AUC 0.795 versus 0.619. A four feature geometry classified activation at ROC AUC 0.996 across 1,336 structures from 199 receptors. Across 207 receptor transducer units, class information was distributed across sequence and structural properties, strongly shaped by evolutionary relatedness, and no universal cross family interface rule emerged. Mature GPCR complexes therefore contain receptor compatibility plus information associated with the selected and stabilized transducer. Similarity to a G protein bound endpoint supports compatibility with that signalling state but does not by itself establish intrinsic coupling preference, a distinction relevant to pathway selective drug discovery.

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Cite

BibTeXRIS
BibTeX
@misc{batebi2026mature,
  title = {{Mature complexes carry more G protein class information than partner free GPCR structures}},
  author = {Hossein Batebi},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009240/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009240/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Mature complexes carry more G protein class information than partner free GPCR structures
AU  - Hossein Batebi
PY  - 2026
DA  - 2026/09/22
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009240/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009240/v1
AB  - GPCR structures are widely used to infer G protein coupling and pathway selective pharmacology, but mature receptor G protein complexes may contain structural information acquired or stabilized after partner selection. We asked how much G protein class information is present independently of the bound transducer. We analyzed 1,360 experimental class A GPCR structures using structural bioinformatics, molecular recognition descriptors and receptor grouped machine learning. Every receptor with both a strict partner free active structure and a G protein bound structure entered the matched analysis; activation and evolutionary transfer served as controls. Twelve receptors met the strict criteria. Bound endpoints gave a larger G protein class margin in 11 of 12 receptors (mean difference 0.389, 95% CI 0.095 to 0.682; exact sign flip P = 0.030), with macro ROC AUC 0.795 versus 0.619. A four feature geometry classified activation at ROC AUC 0.996 across 1,336 structures from 199 receptors. Across 207 receptor transducer units, class information was distributed across sequence and structural properties, strongly shaped by evolutionary relatedness, and no universal cross family interface rule emerged. Mature GPCR complexes therefore contain receptor compatibility plus information associated with the selected and stabilized transducer. Similarity to a G protein bound endpoint supports compatibility with that signalling state but does not by itself establish intrinsic coupling preference, a distinction relevant to pathway selective drug discovery.
ER  -