Dissecting the allosteric networks governing agonist efficacy and potency in G protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) translate binding of extracellular ligands into intracellular responses through conformational changes. Ligand properties are described by the maximum response (efficacy) and the agonist concentration at half-maximal response (potency). Integrating structural changes with pharmacological properties remains challenging and has not yet been performed at the resolution of individual amino acids. We use epinephrine and β2-adrenergic receptor as a model to integrate residue-level pharmacology data with intramolecular residue contact data describing receptor activation. This unveils the allosteric networks driving ligand efficacy and potency. We provide detailed insights into how structural rearrangements are linked to fundamental pharmacological properties at single-residue level in a receptor-ligand system. Our approach can be used to determine such pharmacological networks for any receptor-ligand complex.

Structure-based discovery of nonopioid analgesics acting through the α 2A -adrenergic receptor

“…2B). Mutations of Y409 6.55 greatly affect norepinephrine, increasing (weakening) G i EC 50 values 500-to 10,000-fold, likely disrupting a key hydrogen bond (40,41); the importance of position 6.55 was previously observed in agonist-induced b 2 AR activation (42)(43)(44). The potencies of '9087 and dexmedetomidine are only modestly worse in Y409 6.55 mutants, and for '9087, the G i E max is even slightly increased.…”