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The \u03b2<jats:sub>3<\/jats:sub>AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off\u2010target activation of \u03b2<jats:sub>1<\/jats:sub>AR and \u03b2<jats:sub>2<\/jats:sub>AR. Interestingly, several \u03b2\u2010blockers, which are antagonists of the \u03b2<jats:sub>1<\/jats:sub>ARs and \u03b2<jats:sub>2<\/jats:sub>ARs, have been reported to exhibit agonist activity at the \u03b2<jats:sub>3<\/jats:sub>AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of \u03b2<jats:sub>3<\/jats:sub>AR agonists with improved selectivity and reduced off\u2010target effects. In this work, we determined the structures of human \u03b2<jats:sub>3<\/jats:sub>AR in complex with the endogenous agonist epinephrine or with a synthetic \u03b2<jats:sub>3<\/jats:sub>AR agonist carazolol, which is also a high\u2010affinity \u03b2\u2010blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D<jats:sup>3.32<\/jats:sup> directly contribute to carazolol's distinct activities as an antagonist for the \u03b2<jats:sub>2<\/jats:sub>AR and an agonist for the \u03b2<jats:sub>3<\/jats:sub>AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective \u03b2<jats:sub>3<\/jats:sub>AR agonists, paving the way for new therapeutic opportunities.<\/jats:p>","DOI":"10.1002\/cplu.202400288","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T08:31:10Z","timestamp":1721809870000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular Mechanism of the \u03b2<sub>3<\/sub>AR Agonist Activity of a \u03b2\u2010Blocker"],"prefix":"10.1002","volume":"89","author":[{"given":"Shuang","family":"Zheng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Membrane Biology Tsinghua-Peking Center for Life Sciences School of Pharmaceutical Sciences Tsinghua University  Beijing 100084 P. R. China"},{"name":"Beijing Frontier Research Center for Biological Structure Tsinghua University  Beijing 100084 P. R. 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