G protein-coupled receptors (GPCRs), which regulate virtually all physiological processes in humans, are the largest class of membrane receptors and are important drug targets. The spectroscopic characterization of GPCRs reveals a complex ensemble, which responds to ligands, allosteric agents, and environmental factors. In particular 19F and 13C NMR, pulsed EPR (DEER) spectroscopy, optical spectroscopy, and radioligand studies allow us to characterize the receptor conformational landscape in terms of key functional states and lifetimes. This ensemble description provides a mechanistic basis for well-known pharmacological phenomena including basal activation, inverse agonism, efficacy, biased signaling, and pre-coupling. Recent studies of the adenosine A2A receptor, a prototypical class A GPCR, will be presented and discussed in terms of consequences to our understanding of the activation process and strategies to targetting GPCRs in drug discovery efforts. In particular, we discuss these results in terms of the concept of response to ligands and conformational selection in GPCR activation, allostery, and partial agonism.

Molecular underpinnings of GPCR pharmacology: An NMR and computational study of the adenosine A2 receptor

254th National Meeting (2017)

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