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The mechanisms and therapeutic potential of such dimerization, however, remain poorly understood. Here, we show that AP-7-168, an optimized derivative of a \u03b2-arrestin-biased negative allosteric modulator of the \u03b2\n                  <jats:sub>2<\/jats:sub>\n                  -adrenergic receptor (\u03b2\n                  <jats:sub>2<\/jats:sub>\n                  AR) that sustains bronchorelaxation in cell and tissue models\n                  <jats:sup>4<\/jats:sup>\n                  , functions as a molecular glue to promote \u03b2\n                  <jats:sub>2<\/jats:sub>\n                  AR homodimerization. Cryo-EM structures reveal a unique binding mode in which two AP-7-168 molecules pack within a pocket formed by transmembrane helices 3, 4, and 5 of two protomers, stabilizing a dimeric conformation that selectively prevents \u03b2-arrestin coupling. In cells, AP-7-168 robustly induces \u03b2\n                  <jats:sub>2<\/jats:sub>\n                  AR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings unveil a novel allosteric mechanism by which a small molecule biases \u03b2\n                  <jats:sub>2<\/jats:sub>\n                  AR signaling through dimerization, highlighting ligand-induced dimerization as a strategy for GPCR modulation.\n                <\/jats:p>","DOI":"10.1101\/2025.10.21.683802","type":"posted-content","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T19:20:15Z","timestamp":1761160815000},"source":"Crossref","is-referenced-by-count":1,"title":["A biased allosteric modulator functions as a molecular glue to induce \u03b2\n                  <sub>2<\/sub>\n                  AR dimerization"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3977-0681","authenticated-orcid":false,"given":"Jiemin","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5132-2064","authenticated-orcid":false,"given":"Teja Nikhil","family":"Peddada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6799-4626","authenticated-orcid":false,"given":"Konstantin E.","family":"Komolov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5880-3725","authenticated-orcid":false,"given":"Francesco","family":"De Pascali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0160-2487","authenticated-orcid":false,"given":"Alexander M.","family":"Garces","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0277-3018","authenticated-orcid":false,"given":"Haoqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-4879","authenticated-orcid":false,"given":"Michael T.","family":"Lerch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Benovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-583X","authenticated-orcid":false,"given":"Jun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5958-3990","authenticated-orcid":false,"given":"Brian 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