A Quantitative Analysis of Beta-Adrenergic Receptor Interactions: Resolution of High and Low Affinity States of the Receptor by Computer Modeling of Ligand Binding Data

TLDR

Affinity states of the beta‑adrenergic receptor are defined by distinct macroscopic dissociation constants, allowing the proportion of receptors in each state to be quantified. The study employed computer modeling of indirect binding data to analyze ligand interactions with the beta‑adrenergic receptor. Antagonists bind uniformly to a single affinity state, whereas agonists exhibit two distinct high‑ and low‑affinity states, with the high‑affinity state closely correlating with agonist intrinsic activity.

Abstract

The properties of ligand binding to the beta-adrenergic receptor have been studied using a computer modeling technique to analyze data obtained by indirect binding methods. Antagonists are shown to bind to the receptor with one homogeneous state of uniform affinity, while agonists manifest heterogeneous binding. For agonists, two distinct binding states are apparent; one of high and one of low affinity. Affinity states of the receptor are characterized by specific macroscopic dissociation constants, and the proportion of total receptors in each state can be determined. The ability of an agonist to activate adenylate cyclase (intrinsic activity) correlates closely with the amount of high affinity state formed in the presence of the agonist (p