Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor.
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ABSTRACT:
SUBMITTER: Zhuang Y
PROVIDER: S-EPMC8089099 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor.
Zhuang Youwen Y Krumm Brian B Zhang Huibing H Zhou X Edward XE Wang Yue Y Huang Xi-Ping XP Liu Yongfeng Y Cheng Xi X Jiang Yi Y Jiang Hualiang H Zhang Cheng C Yi Wei W Roth Bryan L BL Zhang Yan Y Xu H Eric HE
Cell research 20210309 5
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Project description:The dopamine D1 receptor (D1R) is a promising target for treating various psychiatric disorders. While upregulation of D1R activity has shown potential in alleviating motor and cognitive symptoms, orthosteric agonists have limitations, restricting their clinical applications. However, the discovery of several allosteric compounds specifically targeting the D1R, such as LY3154207, has opened new therapeutic avenues. Based on the cryo-EM structures of the D1R, we conducted molecular dynamics simulations to investigate the binding and allosteric mechanisms of LY3154207. Our simulations revealed that LY3154207 preferred the horizontal orientation above intracellular loop 2 (IL2) and stabilized the helical conformation of IL2. Moreover, LY3154207 binding induced subtle yet significant changes in key structural motifs and their neighboring residues. Notably, a cluster of residues centered around the Na + binding site became more compact, while interactions involving the PIF motif and its neighboring residues were loosened upon LY3154207 binding, consistent with their role in opening the intracellular crevice for receptor activation. Additionally, we identified an allosteric pathway likely responsible for the positive allosteric effect of LY3154207 in enhancing Gs protein coupling. This mechanistic understanding of LY3154207's allosteric action at the D1R pave the way for the rational design of more potent and effective allosteric modulators.
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