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Publication Abstract from PubMed

Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three beta-adrenergic receptors (betaARs). The beta3AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of beta1AR and beta2AR. Interestingly, several beta-blockers, which are antagonists of the beta1ARs and beta2ARs, have been reported to exhibit agonist activity at the beta3AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of beta3AR agonist drugs with improved selectivity and reduced off-target effects. In this work, we determined the structures of human beta3AR in complex with the endogenous agonist epinephrine or with a synthetic beta3AR agonist carazolol, which is also a high-affinity beta-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D3.32 directly contribute to carazolol's distinct activities as an antagonist for the beta2AR and an agonist for the beta3AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective beta3AR agonists, paving the way for new therapeutic opportunities.

Molecular Mechanism of the beta3AR Agonist Activity of a beta-Blocker.,Zheng S, Zhang S, Dai S, Chen K, Gao K, Sun X, Lin B, Liu X Chempluschem. 2024 Jul 24:e202400288. doi: 10.1002/cplu.202400288. PMID:39046191^[1]

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