A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.

ABSTRACT: Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD₃R:Gα_Oβγ complex bound to the D₃R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal or

SUBMITTER: Arroyo-Urea S 

PROVIDER: S-EPMC11377762 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature