Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41467-026-75728-9

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Despite remarkable advances in human genomics, most rare disorders remain undiagnosed, mechanistically obscure, and without effective treatments. In this study, we establish DRD1, encoding the dopamine D1 receptor (D1R), as a monogenic cause of an infantile-onset dystonia syndrome, for which pharmacological responsiveness may vary depending on the underlying molecular mechanism. Across three unrelated families, eight affected individuals exhibited generalised dystonia, axial hypotonia, and cognitive impairment and carried homozygous pathogenic missense DRD1 variants.

Live-cell biosensor assays revealed that patient-derived DRD1 variants disrupt receptor integrity through mechanistically diverse failures, such as trafficking deficits and impaired agonist-induced activation—ultimately converging on a collapse of D1R-mediated signalling. In line with standard clinical practice and informed by these mechanistic insights, we initiated a trial of levodopa/carbidopa in two individuals in the index family with a partial-loss-of-function variant, which was associated with improvement in voluntary motor function and cognitive engagement. Moreover, in live-cell assays, we demonstrated that Mevidalen—a selective DRD1-positive allosteric modulator currently in clinical development—substantially improved signaling in patient-derived mutants in vitro, supporting a potential future mechanism-aligned therapeutic avenue.

To broaden the clinical implications of our findings, we performed a structural interpretation of DRD1 variation in 807,162 individuals and identified 29 rare predicted deleterious missense variants in heterozygous carriers. These variants clustered within evolutionarily conserved transmembrane domains and signaling motifs, providing a basis for pathogenicity assignment and variant prioritization in clinical and research settings.

Building on these insights, we developed a structure-informed pharmacological experimental framework that stratifies DRD1 variants according to molecular dysfunction and matches them with mechanistically aligned therapeutic strategies—namely, orthosteric agonists, pharmacological chaperones, allosteric modulators, and readthrough compounds. This in vitro approach enabled functional rescue of otherwise intractable variants, suggesting a potentially actionable molecular architecture across diverse genotypes, which remains to be tested clinically.

Together, these findings identify biallelic DRD1 variants as a cause of infantile dystonia and support the potential for mechanism-informed therapeutic exploration, while emphasizing that clinical responsiveness may vary across individuals. More broadly, our integrated genomics-structure-pharmacology framework provides a proof-of-concept approach to functionally stratify G protein-coupled receptor (GPCR) variants, exemplified here by DRD1, and prioritise testable, mechanism-based therapeutic hypotheses for future evaluation.

DOI： 10.1093/brain/awag128

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/jacs.6c02372

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Proceedings of the National Academy of Sciences  

The human adenosine A _2A receptor (A _2A R) is a prototypical member of the class A family of G Protein–Coupled Receptors (GPCRs), which are engaged by over one-third of FDA-approved drugs. Here, we used ¹⁹ F NMR to simultaneously evaluate functional states from the perspective of a CF ₃ -tag on transmembrane helix-6 (TM6) and all 5-fluorotryptophan reporters. Whereas spectra from the TM6 tag reveal a dynamic conformational ensemble, the tryptophan spectra exhibit more discrete ligand-dependent states. These ligand-dependent signatures provide insights into microswitches including a universal toggle switch which interfaces with a sodium binding pocket. Over 560 GPCRs share this toggle switch — sodium pocket cluster, implying a fundamental role in activation. Computational rigidity-theory reveals tryptophan reporters reside along prominent allosteric activation pathways, underscoring their roles in mechanical signal propagation and corroborating NMR observations. Among them, W246 ^6.48 , associated with the toggle switch, plays a critical role in regulation of allosteric networks spanning the orthosteric pocket and extending via tryptophan-rich pathways through the receptor to the A _2A R-Gβ interface and the nucleotide pocket in G _s α. While higher sodium concentrations (~100 mM) predictably stabilize the inactive conformation of the receptor, lower concentrations (below 40 mM) greatly enhanced the presence of the activation ensemble and in particular, the precoupled state, suggesting that the release of sodium from the conserved pocket—either through basal conditions for the apo receptor, or upon binding of the agonist—enables sampling of a precoupled state, ultimately needed to initiate activation and coupling.

DOI： 10.1073/pnas.2525502123

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acsomega.5c08560

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Event date： 2025.11

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2025.9

Language：English   Presentation type：Oral presentation (invited, special)  

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Presentation type：Oral presentation (invited, special)  

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Presentation type：Oral presentation (general)  

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