The molecular basis of Gs protein efficacy at the b2- adrenoceptor

Harwood, Clare (2022) The molecular basis of Gs protein efficacy at the b2- adrenoceptor. PhD thesis, University of Nottingham.

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GPCRs are the largest family of transmembrane receptors in the human genome and currently represent 34% of all FDA approved medicines. The β2-adrenoceptor (β2AR) is a prototypical class A GPCR which is therapeutically relevant in asthma, whereby β2AR agonists relieve bronchoconstriction. Despite the therapeutic importance of the β2AR and other GPCRs the molecular basis of agonist efficacy is not well understood.

The hypothesis underlying this study was that ligand residence time effects b2AR receptor conformational dynamics to affect efficacy of Gs protein activation. To this end, this thesis investigated b2AR agonist ligand binding kinetics and purified mini-Gs binding kinetics to b2AR that had been extracted from the mammalian cell membrane using detergent. This study found no correlation between ligand residence time and Gs protein efficacy for b2AR agonists but found differences in the affinity of full agonist bound b2AR complexes for the mini-Gs compared to partial agonist bound complexes.

These results do not support a role for kinetics in the molecular basis of efficacy at the b2AR but suggest a model in which agonists of higher efficacy stabilise a conformation of the b2AR which is more likely to recruit a Gs protein. Moreover, this thesis shows the development and application of novel methods to study isolated GPCR dynamics and pharmacology. Further application of this approach to a greater number of GPCRs and agonists would elucidate if the model presented in this study is relevant to other receptors and if this shows a general mechanism of efficacy.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Veprintsev, Dmitry
Briddon, Stephen
Keywords: β2-adrenoceptor, β2AR, Gs protein efficacy
Subjects: Q Science > QP Physiology > QP501 Animal biochemistry
R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 71634
Depositing User: Harwood, Clare
Date Deposited: 27 Oct 2022 13:20
Last Modified: 27 Oct 2022 13:20

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