9T7P

Cryo-EM structure of ESG-2-36-bound D3 dopamine receptor with mini-Go

This is a non-PDB format compatible entry.

Summary for 9T7P

• Entry DOI: 10.2210/pdb9t7p/pdb
• EMDB information: 55650
• Descriptor: D(3) dopamine receptor,Lgbit, Engineered miniGo,Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 167705.37

Authors

Yardeni, E.H.,Kiss, D.J.,Keseru, G.M.,Shalev-Benami, M. (deposition date: 2025-11-11, release date: 2026-09-09)

Primary citation

Hadas Yardeni, E.,Kiss, D.J.,Sanchez, J.,Shavit, K.,Szepesi Kovacs, D.,Egyed, A.,Vogt, C.D.,Gaitonde, S.A.,Glenn, J.,Canals, M.,Bouvier, M.,Newman, A.H.,Lane, J.R.,Keseru, G.M.,Shalev-Benami, M.
The structure of the dopamine D 3 receptor bound to cariprazine reveals principles for partial agonists with designed pharmacology.
Sci Adv, 12:eaef7411-eaef7411, 2026

PubMed Abstract: 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.

PubMed: 42664351
DOI: 10.1126/sciadv.aef7411

Experimental method

ELECTRON MICROSCOPY (2.85 Å)