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TitleA Ligand-Triggered Receptor Conformation Enables the Design of Selective Agonists for the Dopamine 3 Receptor (DR) Using a Bitopic Strategy.
Journal, issue, pagesJACS Au, Vol. 6, Issue 7, Page 4138-4152, Year 2026
Publish dateJul 27, 2026
AuthorsSandra Arroyo-Urea / Antonina L Nazarova / Alexander Knieb / Hawau Abdulsalam / Khorshada Jahan / Ting Du / Song Gao / Amy Hauck Newman / Vsevolod Katritch / Javier García-Nafría / Alessandro Bonifazi /
PubMed AbstractWhile G protein-coupled receptors (GPCRs) represent the largest drug target family, designing subtype-selective molecules is still a challenge, especially to distinguish among closely related ...While G protein-coupled receptors (GPCRs) represent the largest drug target family, designing subtype-selective molecules is still a challenge, especially to distinguish among closely related subtypes. One of the most challenging cases is the distinction between dopamine DR and DR, pivotal receptors in motor functions and cognition, and targets of Parkinson's disease treatments, schizophrenia, or substance use disorders. Attempts to design DR-selective molecules with ligands binding toward the first transmembrane helix (the most sequence-diverse and conformationally flexible segment in GPCRs but rarely participating in ligand binding) allowed us to discover a ligand-induced ordering of TM1 unique to DR, yielding an unexploited selectivity site for drug development. Using rational bitopic drug design and the ligand-triggered conformation of the DR we designed, synthesized, and characterized the most selective DR agonists to date, >100,000-fold more selective than available ligands. More specifically, we report DR partial agonists AB12-82 () and AB13-73A (), with >575,000- and >750,000-fold subtype selectivity, picomolar potency, and 85% and 49% efficacy, respectively. We also present the most selective full agonists reported to date, AB13-08 () and AB13-46A (), presenting low and subnanomolar potencies with >2,800- and 6,300-fold selectivity for DR. Overall, we introduce a first-in-class pharmacological toolbox to dissect the (patho)-physiology of DR, open new avenues for the design of improved neurotherapeutics, and show that using ligand-induced TM1 reorganizations might represent a promising strategy for the design of subtype-selective molecules in other GPCRs.
External linksJACS Au / PubMed:42529391 / PubMed Central
MethodsEM (single particle)
Resolution3.47 Å
Structure data

58252

31bg

EMDB-58252, PDB-31bg:
Cryo-EM structure of Dopamine 3 receptor:Go complex bound to bitopic AB13-46A
Method: EM (single particle) / Resolution: 3.47 Å

Chemicals

PDB-1j83:
STRUCTURE OF FAM17 CARBOHYDRATE BINDING MODULE FROM CLOSTRIDIUM CELLULOVORANS

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • aequorea victoria (jellyfish)
KeywordsMEMBRANE PROTEIN / Bitopic molecules / dopamine receptor / drug selectivity / structure-based drug design / GPCRs / G protein-coupled receptors / ligand-triggered receptor conformation

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