{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:50:30Z","timestamp":1787878230835,"version":"build-2784847793"},"reference-count":44,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,7,7]],"date-time":"2024-07-07T00:00:00Z","timestamp":1720310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The \u03b23-adrenoceptor agonist mirabegron is available for the treatment of storage symptoms of overactive bladder, including frequency, urgency, and incontinence. The off-target effects of mirabegron include binding to \u03b11-adrenoceptors, which are central in the treatment of voiding symptoms. Here, we examined the structure\u2013function relationships in the binding of mirabegron to a cryo-electron microscopy structure of \u03b11A. The binding was simulated by docking mirabegron to a 3D structure of a human \u03b11A-adrenoceptor (7YMH) using Autodock Vina. The simulations identified two binding states: slope orientation involving 10 positions and horizontal binding to the receptor surface involving 4 positions. No interactions occurred with positions constituting the \u03b11A binding pocket, including Asp-106, Ser-188, or Phe-312, despite the positioning of the phenylethanolamine moiety in transmembrane regions close to the binding pocket by contact with Phe-288, -289, and Val-107. Contact with the unique positions of \u03b11A included the transmembrane Met-292 during slope binding and exosite Phe-86 during horizontal binding. Exosite binding in slope orientation involved contact of the anilino part, rather than the aminothiazol end, to Ile-178, Ala-103, and Asn-179. In conclusion, contact with Met-292 and Phe-86, which are unique positions of \u03b11A, accounts for mirabegron binding to \u03b11A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to \u03b11A-blockers and no effects on voiding symptoms.<\/jats:p>","DOI":"10.3390\/ijms25137468","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T12:21:03Z","timestamp":1720441263000},"page":"7468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ligand\u2013Receptor Interactions and Structure\u2013Function Relationships in Off-Target Binding of the \u03b23-Adrenergic Agonist Mirabegron to \u03b11A-Adrenergic Receptors"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0770-0726","authenticated-orcid":false,"given":"Ru","family":"Huang","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"Yu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4659-2262","authenticated-orcid":false,"given":"Alexander","family":"Tamalunas","sequence":"additional","affiliation":[{"name":"Department of Urology, LMU University Hospital, LMU Munich, 80539 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian G.","family":"Stief","sequence":"additional","affiliation":[{"name":"Department of Urology, LMU University Hospital, LMU Munich, 80539 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Hennenberg","sequence":"additional","affiliation":[{"name":"Department of Urology, LMU University Hospital, LMU Munich, 80539 Munich, Germany"},{"name":"Urologische Klinik und Poliklinik, Marchioninistr. 15, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1124\/pharmrev.121.000523","article-title":"Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders","volume":"75","author":"Michel","year":"2023","journal-title":"Pharmacol. 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