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Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect underlying the ligand efficacy
  • Ongun Onaran,
  • Tommaso Costa
Ongun Onaran
Ankara University Faculty of Medicine

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Tommaso Costa
Istituto Superiore di Sanità
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Background and Purpose: The classical theory of receptor action has been used for decades as a powerful tool to estimate molecular determinants of ligand-induced receptor activation (i.e. affinity and efficacy) from experimentally observable biological responses. However, it is also a well-recognized fact that the receptor-binding and activation mechanisms, and the parameters thereof, described in the classical theory contradict with the modern view of receptor activation based on allosteric principles. Experimental Approach: We used mathematical analysis, along with some numerical simulations, to answer the key question as to what extent the classical theory is compatible -if at all- with the modern understanding of receptor activation. Key Results: Here, we showed conclusively that 1) receptor activation equations based on allosteric principles contain the logic of the classical theory in disguise, and therefore, 2) estimates of “intrinsic efficacy” () obtained by means of classical techniques (i.e. null methods or fitting the operational model to concentration-response data) are equivalent to the allosteric coupling factors that represent the molecular efficacy of ligands. Conclusion and Implications: Thus, we conclude that despite the right criticisms it has received so far, the classical theory may continue to be useful in estimating ligand efficacy from experimental data, if used properly. Here, we also provide rigorous criteria for the proper use of the theory. These findings not only have implications on ligand classification, but also resolve some long lasting discussions in the field of bias agonism in GPCR, which requires reasonable estimates of relative ligand efficacies at different signalling pathways.
14 Sep 2023Submitted to British Journal of Pharmacology
14 Sep 2023Assigned to Editor
14 Sep 2023Submission Checks Completed
14 Sep 2023Review(s) Completed, Editorial Evaluation Pending
15 Sep 2023Reviewer(s) Assigned
14 Oct 2023Editorial Decision: Revise Minor