Constrained catecholamines gain β₂AR selectivity through allosteric effects on pocket dynamics.

ABSTRACT: G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β₁ and β₂ adrenergic receptors (β₁AR and β₂AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β₂AR over the β₁AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β₂AR, as well as a less stabl

SUBMITTER: Xu X 

PROVIDER: S-EPMC10104803 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature