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TitleThe structure of the dopamine D receptor bound to cariprazine reveals principles for partial agonists with designed pharmacology.
Journal, issue, pagesSci Adv, Vol. 12, Issue 35, Page eaef7411, Year 2026
Publish dateAug 28, 2026
AuthorsEliane Hadas Yardeni / Dóra Judit Kiss / Julie Sanchez / Keshet Shavit / Dénes Szepesi Kovács / Attila Egyed / Caleb D Vogt / Supriya A Gaitonde / Jacqueline Glenn / Meritxell Canals / Michel Bouvier / Amy Hauck Newman / J Robert Lane / György M Keserű / Moran Shalev-Benami /
PubMed AbstractThe third-generation antipsychotic cariprazine is a low-efficacy partial agonist of the dopamine D receptor (DR). Here, we report the cryo-electron microscopy structure of cariprazine bound to DR, ...The third-generation antipsychotic cariprazine is a low-efficacy partial agonist of the dopamine D receptor (DR). Here, we report the cryo-electron microscopy structure of cariprazine bound to DR, establishing a framework for understanding ligand recognition in this receptor. We further determine structures of DR in complex with a series of cariprazine derivatives spanning inverse agonists to high-efficacy partial agonists. Integration of structural data with pharmacological profiling and molecular dynamics simulations reveals how subtle chemical modifications translate into distinct functional outcomes. Determinants distinguishing agonism from inverse agonism are well defined, whereas differences among partial agonists arise from small positional shifts of the ligand within the orthosteric binding site. In contrast, the extended binding site primarily modulates ligand stability, affinity, and receptor selectivity. These findings establish a mechanistic link between bitopic ligand architecture and receptor activation, providing a "ligand-centric" view of DR signaling. Leveraging these principles, we designed and validated cariprazine derivatives with enhanced D/D selectivity and partial agonist activity. Together, this work provides a structural and pharmacological blueprint for the rational design of DR-targeting ligands with tailored efficacy and therapeutic profiles.
External linksSci Adv / PubMed:42664351 / PubMed Central
MethodsEM (single particle)
Resolution2.85 Å
Structure data

55650

9t7p

EMDB-55650, PDB-9t7p:
Cryo-EM structure of ESG-2-36-bound D3 dopamine receptor with mini-Go
Method: EM (single particle) / Resolution: 2.85 Å

Chemicals

PDB-1jua:
Solution Structure of the Deoxyribose HIV-1Lai Initiation Sequence Stable Dimer

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / agonist

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