Multiple allosteric sites allow for synergistic enhancement of GPCR signaling. (PubMed, Sci Adv) - Oct 23, 2026 - "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."
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Abhishek Thakur; Alexander Goldberg; Amy E Moritz; Ashley N Nilson; Bing Xie; David R Sibley; Feijun Wang; H Eric Xu; Jayachandra Rayadurgam; Jian Zhang; John N Hanson; Kai Wang; Kathryn D Luderman; Kevin J Frankowski; Lei Shi; R Benjamin Free; Snezana T Dimova; Wen Hu; Yini Liu; Youwei Xu; Youwen Zhuang; Yue Wang
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