Agonists in the Extended Conformation Stabilize the Active State of β-Adrenoceptors

Abstract In this study, we conducted a comparative analysis of the structure of agonists and antagonists of transmembrane (TM) β-adrenoceptors (β-ARs) and their interactions with the β-ARs and proposed the mechanism of receptor activation. A characteristic feature of agonist and antagonist molecules is the presence of a hydrophobic head (most often, one or two aromatic rings) and a tail with a positively charged amino group. All β-adrenergic agonists have two carbon atoms between the aromatic ring of the head and the nitrogen atom of the amino group. In antagonist molecules, this fragment can be either reduced or increased to four atoms due to the additional carbon and oxygen atoms. The agonist head, as a rule, has two H-bond donors or acceptors in the para - and meta -positions of the aromatic rings, while in the antagonist heads, these donors/acceptors are absent or located in other positions. Analysis of known three-dimensional structures of β-AR complexes with agonists showed that the agonist head forms two H-bonds with the TM5