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We developed two novel D1R positive allosteric modulators (PAMs), UNC9815 and UNC10062, and used cryo\u2013electron microscopy to structurally identify two previously uncharacterized D1R allosteric sites occupied by UNC9815\/UNC10062 and another D1R PAM, BMS-A1. Both sites localize to the transmembrane helix (TM) 1 to 7 interface as vertically adjacent allosteric pockets organized in a spatially complementary manner. Our structures demonstrate the simultaneous binding of the chemically distinct PAMs (LY3154207, BMS-A1, and UNC9815\/UNC10062) in three nonoverlapping pockets. Concurrent engagement of all three allosteric sites produces pronounced functional cooperativity, increasing dopamine potency by &gt;1000-fold, thereby demonstrating that coordinated multisite modulation can achieve substantial pharmacological amplification beyond the limits imposed by single PAM administration. Molecular dynamics (MD) simulations revealed that multisite PAM engagement restricts intracellular loop 3 dynamics and stabilizes the TM7-NPxxY activation motif, effects not achieved by binding of LY3154207 alone, thereby biasing the receptor toward a more stabilized active conformation, and may also improve agonist potency by stabilizing extracellular loop 2. Together, these findings establish the structural framework for cooperative multisite allostery in a GPCR, revealing how distributed allosteric sites act in concert to amplify receptor activation and providing a conceptual foundation for developing innovative GPCR allosteric therapeutics.<\/jats:p>","DOI":"10.1126\/sciadv.aeh3401","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:01:42Z","timestamp":1792605702000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Multiple allosteric sites allow for synergistic enhancement of GPCR signaling"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2620-448X","authenticated-orcid":true,"given":"Kai","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 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