Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

Beta adrenergic receptors (beta ARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds beta(1)AR and beta(2)AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the beta(1)AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human beta(1)AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between beta(1)AR and beta(2)AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.

Automated summary

Beta adrenergic receptors mediate physiological responses to catecholamines epinephrine and norepinephrine, and norepinephrine shows higher affinity for beta(1)AR. Crystal structure analysis revealed identical catecholamine-binding pockets but differences in extracellular vestibules between beta(1)AR and beta(2)AR, influencing norepinephrine binding path and affinity.