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Publication Abstract from PubMed

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 beta(1) and beta(2) adrenergic receptors (beta(1)AR and beta(2)AR) 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 beta(2)AR over the beta(1)AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the beta(2)AR, as well as a less stable binding pocket for constrained epinephrine in the beta(1)AR. The differences in the amino acid sequence of the extracellular vestibule of the beta(1)AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the beta(2)AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.

Constrained catecholamines gain beta(2)AR selectivity through allosteric effects on pocket dynamics.,Xu X, Shonberg J, Kaindl J, Clark MJ, Stossel A, Maul L, Mayer D, Hubner H, Hirata K, Venkatakrishnan AJ, Dror RO, Kobilka BK, Sunahara RK, Liu X, Gmeiner P Nat Commun. 2023 Apr 14;14(1):2138. doi: 10.1038/s41467-023-37808-y. PMID:37059717^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.