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

Alexander V. Efimov1,a*, Olga V. Meshcheryakova2,b, and Alexey G. Ryazanov3,c

1Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

2Institute of Biology of the Karelian Research Centre of the Russian Academy of Sciences, 185910 Petrozavodsk, Russia

3Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, 08854 New Jersey, USA

* To whom correspondence should be addressed.

Received March 21, 2022; Revised June 21, 2022; Accepted June 21, 2022
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 helix, and the tail forms an ionic bond with the D3.32 residue of the TM3 helix and one or two H-bonds with the TM7 helix. The tail of the antagonist can form similar bonds, but the interaction between the head and the TM5 helix is much weaker. As a result of these interactions, the agonist molecule acquires an extended “strained string” conformation, in contrast to the antagonist molecule, which has a longer, bended, and flexible tail. The “strained string” of the agonist interacts with the TM6 helix (primarily with the W6.48 residue) and turns it, which leads to the opening of the G protein-binding site on the intracellular side of the receptor, while flexible and larger antagonist molecules do not have the same effect on the receptor.
KEY WORDS: β-adrenoceptor, GPCR, agonist, antagonist, activation mechanism

DOI: 10.1134/S0006297922070057